Granulicatella infections: Comprehensive review of an elusive opportunistic pathogen

Abstract

Granulicatella species, previously classified as nutritionally variant streptococci, have emerged as important opportunistic pathogens. Although typically part of the normal oral, gastrointestinal, and genitourinary flora, these fastidious Gram-positive cocci can cause serious infections in both immunocompetent and immunocompromised individuals. Their identification often proves difficult due to slow growth and unusual nutritional requirements, which limit the reliability of conventional culture methods. This narrative review consolidates data from over 100 case reports and clinical studies to present a comprehensive overview of Granulicatella infections. Infective endocarditis appears as the most frequently reported and life-threatening condition, often affecting the aortic and mitral valves. Patients with prosthetic valves or congenital heart defects face a higher risk. Delayed diagnosis frequently results in complications such as heart failure, systemic emboli, and renal dysfunction. Granulicatella species also contribute to osteomyelitis, pulmonary infections, brain abscesses, gastrointestinal sepsis, and infections related to implanted medical devices. Effective management typically involves beta-lactam antibiotics combined with aminoglycosides, although antimicrobial resistance remains a concern. Surgical intervention often proves necessary, especially in cases with prosthetic material or severe complications. Outcomes are generally favorable when infections are identified early and managed effectively. However, delayed recognition and suboptimal therapy continue to contribute to poor prognoses in some patients. This review emphasizes the need to improve clinical awareness and establish standardized diagnostic and therapeutic approaches to address the challenges posed by Granulicatella infections.

Key Words: Granulicatella; Infective endocarditis; Opportunistic pathogen; Nutritionally variant streptococci; Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; Antibiotic resistance; Osteomyelitis; Septic shock; Molecular diagnostics; Biofilm infections

Core Tip: Granulicatella species, formerly known as nutritionally variant streptococci, are increasingly recognized as significant pathogens in infective endocarditis and other systemic infections. This narrative review synthesizes published case reports and series to highlight the diverse clinical manifestations, diagnostic challenges, and treatment outcomes associated with Granulicatella and Abiotrophia infections. By underscoring the rarity and complexity of these organisms, this work emphasizes the need for heightened clinical awareness and more standardized diagnostic approaches.

INTRODUCTION

Nutritionally variant streptococci (NVS) were first discussed and classified by Frenkel and Hirsch in 1961. Their research showed that these bacteria had unusual nutritional requirements including, pyridoxal hydrochloride and L-cysteine for optimal growth[1]. Recent developments in molecular biology have led to their reclassification. Based on 16s ribosomal RNA (rRNA) gene sequencing, NVS are now classified into two genera: Abiotrophia and Granulicatella[2]. This new classification marks a significant step in understanding these bacteria and provides a more transparent taxonomic framework. Currently, the genus Granulicatella consists of Granulicatella adiacens, G. elegans and G. balaenopterae, whereas the genus Abiotrophia only has Abiotrophia defectiva[3].

Granulicatella species are part of normal human flora and are usually found in the oral cavity, gastrointestinal (GIT) tract, and genitourinary tract[4]. These Gram-positive cocci often form chains and show facultative anaerobic characteristics. They may show a satellite growth pattern when cultured alongside specific bacteria, particularly Staphylococcus aureus[1]. Due to their thin and fragile cell walls, fastidious growth requirements, and slow replication rates, their microscopic identification is often complicated, leading to negative culture results[5]. Molecular diagnostic techniques, in the form of 16S rRNA gene sequencing and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), have significantly improved the identification of these bacteria[2]. However, diagnostic challenges still exist, pointing out the need for further research on the Granulicatella infections and new diagnostic techniques. Granulicatella species pose significant diagnostic difficulties due to their fastidious growth requirements and slow replication, often leading to false-negative cultures. In such cases, advanced molecular methods like MALDI-TOF MS and 16S rRNA gene sequencing are critical, particularly in culture-negative endocarditis, polymicrobial infections, prosthetic device-related infections, and immunocompromised patients with atypical presentations. These techniques offer superior sensitivity and specificity, enabling rapid and accurate identification essential for early intervention. MALDI-TOF MS provides species-level results within hours, while 16S rRNA sequencing resolves ambiguous cases through genetic comparison with reference databases. Their timely use significantly improves diagnostic confidence and patient outcomes[5,6].

Although generally viewed as commensals, these bacteria have been recognized as potent pathogens in both immunocompetent and immunosuppressed individuals[7]. Granulicatella species is found to cause a lot of infections. The most well-known condition is infective endocarditis (IE). Other associated infections include osteomyelitis, GIT infections, urinary tract infections (UTIs), brain abscesses, septic arthritis, septic shock, and rarer occurrences such as lingual abscesses, tubo-ovarian infections, and peritonitis in patients undergoing continuous ambulatory peritoneal dialysis (CAPD).

While a decent number of case reports and studies discuss the pathogenic potential of Granulicatella species, the existing literature remains in bits and pieces. To date, no comprehensive review systematically combines the varied clinical manifestations, treatments, and outcomes related to this genus. In this review, we have examined a variety of clinical presentations, different issues in the diagnosis, interventions, and outcomes to create a coherent understanding of infections caused by Granulicatella species.

A thorough investigation of case reports and case series was conducted on the databases of PubMed, ScienceDirect, Scopus and the Cochrane Library from their inception until April 2025. The search query utilized the keywords “Granulicatella”, “Abiotrophia”, “infections”, “endocarditis”, “organ system involvement”, and “systematic manifestations”. The search strategy involved the use of the Boolean operator “AND” and “OR” to merge the medical subject headings and text keywords. Additionally, a manual search of existing literature was conducted by two researchers independently to identify pertinent case reports and case series. Our narrative review integrated relevant published case reports and case series. The study incorporated full-text articles and only included abstracts if they contained sufficient information. Studies that lacked adequate data or were not related to Granulicatella were excluded. Only articles published or available in the English language were included. The utilization of inclusion criteria was employed to exclude obsolete references and include studies of significant relevance.

IE

Granulicatella species, a group of fastidious, NVS, most commonly present as IE. Infections typically develop insidiously and lead to a delay in diagnosis and treatment. Granulicatella IE primarily involves the aortic and mitral valves. Prosthetic valves and valves with structural defects are also uniquely susceptible to these bacteria. Patients often present with nonspecific symptoms such as fever, malaise, and fatigue. Classic signs of infection may be absent altogether, manifesting late in the course of illness. The organism grows slowly and cultures may yield inconsistent results. Diagnosis usually requires a combination of clinical criteria and more advanced microbiological technologies[8,9].

Looking at the cases of IE caused by Granulicatella species produces several interesting clinical patterns. Granulicatella infections are typically seen as subacute in both adults and children. This subacute pattern is underscored in several case reports, demonstrating the need for clinicians to have a heightened suspicion of IE, particularly in patients with prosthetic valves or cardiac devices in situ[10]. Several reports discussed infections involving the aortic valve, largely consistent with the known predilection of Granulicatella species for high-pressure valves[11-14]. The aortic valve was primarily targeted, although pulmonary and tricuspid valve involvement was also reported[6,11,12]. Cases of pulmonary valve homograft infections in children, suggesting that congenital heart disease and implanted devices may alter or modify typical infective patterns, have also been reported[15-17]. However, multiple case reports and case series have demonstrated the polymorphic clinical presentations and varied outcomes of G. adiacens infections, calling for timely recognition and multi-faceted medical and surgical treatment[18-20].

A few cases of Granulicatella endocarditis revealed consistent worrisome trends. In these cases, mortality rate was exceedingly high, with 5 of 6 patients dying despite adequate antibiotic therapy. Mitral and aortic valve vegetations contributed to serious debilitation of organ systems, including heart failure, glomerulonephritis, and pseudoaneurysm. Renal complications were also common in several patients, where they often required dialysis or contributed to patient demise[21-25].

The majority of diagnoses were established with the help of blood cultures and modified Duke criteria. Echocardiogram evidence of vegetation was not always detected, making the diagnostic process difficult[11,13,26]. This stresses the importance of microbiological and clinical findings rather than only echocardiogram findings. The diagnosis is not always straight forward and atypical symptoms like sacroiliitis[12,27] points towards several differentials until the final one is made. Advanced diagnostic methods, such as next-generation sequencing (NGS), have rendered great assistance in confirming the presence of G. adiacens as the infecting organism in particular culture-negative situations[28-30]. The diagnostic yield of Granulicatella endocarditis is markedly enhanced by molecular techniques. NGS offers distinct advantages, particularly in cases presenting with negative blood cultures yet positive polymerase chain reaction findings from valvular tissue, systemic embolization of unclear origin such as cerebrovascular events or splenic abscesses, and infections involving prosthetic valves where biofilm formation impedes microbial recovery. Podgórska et al[28] illustrated the utility of NGS in detecting G. adiacens from excised valvular tissue despite culture negativity, facilitating organism-specific treatment and favorable clinical outcomes. Likewise, MALDI-TOF MS substantially shortens identification time from several days to mere hours, an essential benefit in managing acute clinical scenarios[13].

Treatment regimen for Granulicatella species, varied from case to case. Several factors including the age, overall health, valvuloplasty status, and condition of the valves before action directly affect the prognosis and the approach of management. For instance, in cases with minimal complications and timely recognition, antibiotic therapy alone was fruitful. Antibiotic therapy mostly consisted of beta-lactam antibiotics (ampicillin, ceftriaxone, penicillin) in combination with an aminoglycoside like gentamicin, mainly during the early phases of treatment[31]. Some resistances to gentamicin was encountered[13], prompting changes in therapy. In some instances, vancomycin was added to the therapy on suspicion of resistance to beta-lactams[11]. In other instances, empirical therapy was started with ampicillin, gentamicin, and vancomycin, followed by specific antibiotics after confirmation of the infection, leading to clinical improvement[32,33].

Even though the majority of patients had resolution of infections, particularly those diagnosed and managed early with targeted antibiotics, surgical interventions were sometimes needed, especially in cases with prosthetic material or related complications, such as damage to the regurgitant valve[7,16,34,35]. For example, in one of the reports, a 20-year-old male with IE that compromised both mitral and aortic valves, was initially difficult to diagnose but treatment was initiated with vancomycin, gentamicin, and rifampicin and the patient ended up needing cardiac surgery[15,36].

Granulicatella infection usually causes systemic embolic complications like femoral embolism caused by G. adiacens IE. The treatment advocates extended periods of antibiotic therapy with embolectomy or valve replacement. There are reports, whereby splenic artery aneurysms developed due to embolic complication secondary to IE[37,38]. Such scenarios point to the very urgent diagnosis and management of embolic events to prevent an organ from being damaged and failing. In addition to the common cardiovascular complications, in some cases patients with subacute IE developed mixed cryoglobulinemia[39,40]. In other reports, patients experienced severe sequelae such as ruptured chordae tendinae, brain abscesses, and osteomyelitis[41,42]. Such cases required a multi-disciplinary approach to care and aggressive therapy to resolve life-threatening complications[42]. Due to severe destruction of valves, surgery became often mandated in cases of abscess and other complications. Thus, with extensive damage to the mitral valve, surgical debridement and valve repair were required in some cases[43,44]. In another case, surgery was emphasized as necessary for prosthetic valve endocarditis in a patient who underwent re-operative aortic valve repair after recurrent infections persisted even after prolonged antibiotic treatment[45,46].

While the prognosis is good for patients with G. adiacens IE as long as aggressive surgical and medicinal options are given in time, there are wide variations in the clinical course pointed out by a case series, where some patients ended up with serious complications and poor outcomes[47,48]. Timely recognition of G. adiacens infection contributes to reduced mortality and enhances recovery rates.

The variegated manifestations about effective antibiotic treatment of Granulicatella infection occurred despite early commencement of antibiotic treatment with cephalosporin, vancomycin, or penicillin, highlighting the virulence and resistance patterns of Granulicatella species. Valve replacements have been conducted surgically in some cases, but they often could not avert mortality. Immunocompromised patients such as kidney transplant recipients were especially susceptible[49]. In this regard, aggressive Granulicatella IE underlines the need for urgent diagnosis, optimal combined medical and surgical treatment, and refined management protocols for high-risk groups.

Granulicatella species, especially G. adiacens, pose a considerable hurdle in the context of IE, quite often involving aortic and mitral valves with adversely severe complications. The high mortality rate denotes the organism’s virulence and resistance patterns, even when treated with appropriate antibiotics. Diagnosis at an early stage, state-of-the-art techniques such as NGS, and a mix of lengthy antibiotic treatment and surgery provide the best hope for improving outcomes for patients. These cases establish the need for increased clinical awareness for Granulicatella-associated IE among immunocompromised and high-risk populations to warrant prompt attention (Table 1).

Table 1 Infective endocarditis.

Ref.	Year	Country	Patient(s)	Sex	Age, years	Granulicatella species	Diagnosis	Valves involved	Intervention(s)	Outcome/prognosis
Jones et al[11]	2018	Georgia	1	Male	70	G. adiacens	Prosthetic valve IE	Aortic	Initially, piperacillin/tazobactam 3.375 g IV every 6 hours, levofloxacin 500 mg IV every 24 hours; then modified to vancomycin 15 mg/kg IV every 12 hours, ampicillin 2 g IV every 4 hours; finally, vancomycin continued and ceftriaxone 2 g IV every 12 hours (substituted for ampicillin)	Good prognosis
Tong et al[8]	2017	China	1	Female	42	G. adiacens and Candida albicans	IE with systematic embolization	Aortic	Initially, empirical ampicillin/sulbactam for fever and abdominal pain; meropenem (500 mg IV every 8 hours) after admission; emergency surgery removed a 4 cm fish bone penetrating the left atrium with large vegetation; after the blood cultures, antimicrobial therapy adjusted to meropenem and voriconazole; after two weeks, therapy switched to moxifloxacin and fluconazole	Good prognosis
Podgórska et al[28]	2022	Poland	1	Male	20	G. adiacens	IE	Mitral and aortic	Initially, empirical vancomycin, gentamicin, and rifampicin for suspected IE; cardiac surgery performed for mitral valve replacement and aortic homograft implantation; arterial-venous extracorporeal membrane oxygenation applied due to multi-organ failure; later, G. adiacens was identified and therapy switched to ceftriaxone and gentamicin	Good prognosis
Rosenthal et al[13]	2002	Germany	1	Male	68	G. adiacens	Vertebral osteomyelitis and IE associated with a pacemaker lead	Not specified; vegetation was adjacent to the pacemaker lead	Bed rest, antibiotics (penicillin, rifampin, gentamicin), and discontinuation of gentamicin due to resistance	Good prognosis
Verdecia et al[9]	2019	United States	1	Male	42	G. adiacens Peptostreptococcus species	Tri-valvular IE	Aortic, mitral, tricuspid	IV penicillin G, gentamicin and later vancomycin added	Scheduled follow-up; potential valve replacement surgery
Warren et al[47]	2023	United States	1	Female	74	G. adiacens	Recurrent IE of a bioprosthetic aortic valve	Bio-prosthetic aortic	Initial treatment with IV ceftriaxone for six weeks; later re-operative aortic valve repair with modified nicks root enlargement; subsequent treatment with IV gentamicin and vancomycin for six weeks	Successful clearance of the bacteria after the second course of antibiotics and surgical intervention
Tang et al[10]	2021	China	1	Male	35	G. adiacens	IE with aortic valve vegetation	Aortic	Initially, teicoplanin with ceftriaxone for six weeks, followed by aortic valve replacement surgery	Good prognosis
Maudlin et al[12]	2022	Australia	1	Male	32	G. adiacens	Subacute IE presenting with right sacroilitis	Aortic	Six weeks course of IV ceftriaxone and a two-week course of synergistic gentamicin	Good prognosis
Sim et al[39]	2015	Australia	1	Male	57	G. adiacens	Subacute IE associated with type II mixed cryoglobulinaemia	Aortic (non-coronary cusps)	Six weeks of benzylpenicillin therapy, followed by aortic valve replacement with a biological prosthesis	Good prognosis
Dao et al[21]	2022	United States	1	Male	69	G. adiacens	Subacute IE presenting as diffuse alveolar hemorrhage and infection-related glomerulonephritis	Mitral (severe regurgitation and vegetation on posterior leaflet)	Ceftriaxone (later transitioned to ampicillin and gentamicin); mitral valve replacement and coronary artery bypass graft; continuous renal replacement therapy, mechanical ventilation, and vasopressor support	Mortality due to complications including cardiogenic shock
De Luca et al[16]	2013	Italy	2	Male, female	5, 7	G. adiacens; G. elegans; Granulicatella balaenopterae	IE based on modified Duke criteria; IE involving the pulmonary valve homograft	No vegetation detected on echocardiography; pulmonary valve homograft	Initial treatment with cefotaxime and gentamicin; switched to ciprofloxacin and meropenem; initial treatment with vancomycin and gentamicin; switched to vancomycin plus meropenem; eventual pulmonary valve homograft replacement	Good prognosis
Shaik et al[22]	2020	United States	1	Male	46	G. albicans	IE and post infectious glomerulonephritis	Mitral (vegetations identified)	IV vancomycin and immunosuppressive therapy; later placed on hemodialysis	Poor prognosis
Patri and Agrawal[43]	2016	United States	1	Male	63	G. elegans	IE with large aortic valve vegetation and associated cervical discitis	Aortic	Initially, vancomycin and ceftriaxone, later switched to ampicillin and ceftriaxone	Mortality due to progressive heart failure
Al-Tawfiq et al[14]	2007	Saudi Arabia	1	Male	47	G. elegans	Native valve IE	Mitral	IV antibiotics (not specified) for 7 days. Mitral valve debridement, repair of perforation, resection of posterior leaflet, and placement of Carpentier-Edwards ring	Good prognosis
Casalta et al[6]	2002	France	1	Male	29	G. elegans	IE	Aortic	Initially, IV amoxicillin and gentamicin, then replacement of aortic valve with bioprosthetic valve	Good prognosis
Vandana et al[25]	2010	India	1	Male	71	G. adiacens	IE with femoral embolism	Mitral	Initially, IV ampicillin (12 g/24 hours) and gentamicin (180 mg/24 hours). Surgical embolectomy (Fogarty’s procedure) for femoral artery thrombus. Antibiotic therapy for a total of five weeks	Good prognosis
Patil et al[41]	2019	United States	1	Female	44	G. adiacens	IE with ruptured chordae tendinae, septic embolization, brain abscess and lumbar spine osteomyelitis	Mitral	IV vancomycin and meropenem. Mitral valve replacement with Hancock type 2 mitral valve tissue. Six-week course of IV vancomycin and ertapenem	Good prognosis
Khan et al[18]	2021	United States	1	Female	73	G. adiacens	IE with severe aortic regurgitation	Aortic	Initially, IV ampicillin (2 g every 6 hours) and ceftriaxone (2 g every 24 hours) for 6 weeks with furosemide	Good prognosis
Adam et al[7]	2015	Brazil	4	Male, male. male, female	31, 64, 75, 59	Not mentioned; G. adiacens; G. adiacens; Not mentioned	IE with complications such as abscess, fistula, embolism, and heart failure	Aortic	Initially, ceftriaxone, oxacillin, and gentamicin; valve replacement surgery; later teicoplanin + gentamicin. Ceftriaxone + oxacillin + gentamicin and valve replacement surgery; later teicoplanin. Penicillin and gentamicin, no surgery. Ceftriaxone + gentamicin; valve replacement surgery; later, vancomycin and gentamicin	Good prognosis; mortality due to complications; mortality due to embolism; good prognosis
Holloway et al[15]	2021	United Kingdom	1	Female	9	G. elegans	IE	Echocardiogram revealed no clear vegetation, but increased stenosis of the right ventricle to pulmonary artery conduit	Initially, benzylpenicillin and cefotaxime, then benzylpenicillin monotherapy for 2 weeks in the hospital followed by 4 weeks of ceftriaxone	Good prognosis
Giuliano et al[32]	2012	Italy	1	Male	40	G. adiacens	IE with vegetation and erosion of aortic valve cusps, periannular abscess, and perivalvular pseudoaneurysm	Aortic	Empirical antibiotic therapy with ampicillin, gentamicin, and vancomycin (vancomycin discontinued after blood culture results). Aortic valve replacement on day 2. Combination therapy with ampicillin (12 g/day) and gentamicin (80 mg every 8 hours) for 4 weeks, followed by an additional 2-week regimen of ampicillin alone	Good prognosis
Paula et al[49]	2017	Brazil	1	Male	67	Granulicatella species	IE of mitral valve in a kidney transplant recipient	Mitral	Initially, ciprofloxacin and metronidazole upon admission. Nitazoxanide (500 mg bid for 7 days) was administered, addressing the cause of diarrhea. The treatment was changed to piperacillin-tazobactam due to persistent fever. Once Granulicatella species was identified in blood cultures, the patient was started on crystalline penicillin G (12000 IU/day, dose adjusted for renal function) and gentamicin (200 mg/day)	Mortality due to septic shock of pulmonary origin
Wang et al[20]	2015	China	1	Female	32	G. eligans	IE	Tricuspid	Initially, IV levofloxacin (750 mg every 24 hours) for 2 days. Then, IV penicillin (800 U every 12 hours) for 13 days based on antibiotic sensitivity testing	Good prognosis
Chang et al[30]	2008	Taiwan	1	Male	31	G. adiacens	IE with infectious intracranial aneurysms and recurrent hemorrhagic stroke	Mitral	Initially, ampicillin/sulbactam for 14 days, followed by oral amoxicillin/clavulanic acid for 2 weeks. Surgical clipping of infectious intracranial aneurysms. Parenteral oxacillin and gentamicin therapy for recurrent intracranial aneurysms. Mitral valvuloplasty performed 5 months after stabilization of neurological function	Full clinical improvement with no further brain insults over a 5 year follow up period
Morita et al[26]	2017	Japan	1	Female	67	G. adiacens	IE associated with primary Sjogren’s syndrome and chronic periodontitis	Aortic	Initially, ampicillin/oxacillin and gentamicin. Adjusted therapy to ampicillin and gentamicin based on antimicrobial susceptibility findings. Aortic valve replacement. Six weeks of ampicillin and gentamicin therapy	Good prognosis
Shailaja et al[19]	2013	India	1	Male	63	G. adiacens	IE with multiple vegetations on the mitral valve	Mitral	Empirical treatment with high-dose IV ampicillin (2 g every 4 hours) and gentamicin (60 mg every 8 hours) for 28 days	Good prognosis
Granda-Jiménez et al[17]	2023	United States	1	Female	8	G. elegans	IE with vegetation attached to the pulmonary trunk in a child with a history of patent ductus arteriosus	None specified; vegetations on pulmonary trunk	Forty days of IV ceftriaxone, followed by vegetation removal percutaneously. Patent ductus arteriosus closed with Amplatzer duct occluder 8/6	Good prognosis
Lin and Hsu et al[48]	2007	Taiwan	4	Female, male, male, female	18, 61, 30, 21	G. adiacens	IE with rheumatic heart disease and heart failure; IE with heart failure; IE with ruptured mycotic cerebral aneurysm; IE with heart failure and limb embolisation	Aortic; mitral and tricuspid; mitral; mitral and tricuspid	Aortic valve replacement with mechanical valve; penicillin and gentamicin. Mitral and tricuspid valve replacement with bioprosthesis; penicillin and gentamicin. Mitral valve repair; penicillin, gentamicin and ceftriaxone. Mitral and tricuspid valve replacement with bioprosthesis; penicillin, gentamicin and teicoplanin.	Good prognosis with no relapse
Rhodes et al[24]	2016	United States	7	Male, female, male, male, female, male, male	50, 25, 48, 60, 89, 31, 30	Abiotrophia defective; Abiotrophia defectiva; G. adiacens; Abiotrophia defectiva; Abiotrophia defectiva; G. adiacens; G. adiacens	Mitral insufficiency, prior dental infection with IE; mitral valve prolapse, prior dental infection, IE; previous mitral valve repair and IE; severe mitral valve insufficiency and IE; history of rheumatic fever with IE; IE; IE	Mitral; mitral; mitral; mitral; mitral; mitral; mitral	Bioprosthetic mitral valve, dual chamber pacemaker, vancomycin, gentamicin, and cerebral angiography. Ceftriaxone, rifampcin, gentamicin, aneurysmal resection, microvascular bypass, mitral valve repair, plication of the posterior leaflet, insertion of new chordae. Penicillin, gentamicin and mitral valve repair. Penicillin, gentamicin, external ventricular drainage and aneurysm clipped. Penicillin and gentamicin. Ampicillin/sulbactum, oxacillin, gentamicin, right middle cerebral artery clipped, mitral valvuloplasty. Penicillin, ceftriaxone, gentamicin, mitral valve repair	Good prognosis
Padmaja et al[31]	2014	India	1	Female	48	G. adiacens	IE	Mitral	Initially, with IV amikacin (1 mg/kg body weight). Definitive treatment with IV ceftriaxone (1 g) and gentamicin (80 mg) twice daily for four weeks	Good prognosis
Farid et al[33]	2019	United States	1	Male	62	G. elegans	IE	Mitral	Mitral valve replacement surgery, followed by 6 weeks of parenteral therapy with vancomycin and gentamicin	Recovery with trivial prosthetic mitral valve regurgitation
Freitas et al[40]	2023	Portugal	1	Male	62	G. adiacens	IE	Aortic	Three weeks of ampicillin and gentamicin followed by aortic valve replacement and interventricular communication repair. Later, extended antibiotics (26 days) for pulmonary valve vegetation due to high surgical risk	Good prognosis
Quiroga et al[23]	2012	Spain	1	Male	86	G. adiacens	IE with associated glomerulopathy	Prosthetic aortic	IV daptomycin (10 mg/kg/48 hours), later switched to ceftriaxone; tooth extraction; no surgical intervention due to age and comorbidities	Patient died after 3 months (Enterococcus species sepsis) due to the permanent catheter
Culleton et al[37]	2016	Ireland	1	Male	35	G. adiacens	IE with embolic stroke and splenic artery aneurysms	Mitral and aortic	Mitral and aortic valve repair surgery, followed by emergency splenectomy	Good prognosis
Rahimi et al[35]	2022	Malaysia	1	Male	19	G. adiacens	IE complicated by left ventricular pseudoaneurysm	Aortic	IV antibiotics prior to collapse and death	Mortality prior to diagnosis
Perkins et al[27]	2003	Spain	1	Male	57	G. adiacens	IE	Aortic and mitral	Ampicillin and gentamicin	Good prognosis
Opperman et al[38]	2020	South Africa	1	Female	29	G. adiacens	IE with stroke and mycotic aneurysm	Mitral	IV penicillin for 4 weeks and gentamycin for 2 weeks	Good prognosis
Prakash et al[46]	2018	India	1	Male	56	G. adiacens	Acute native valve endocarditis	Mitral	IV ceftriaxone 2 g once daily and gentamycin 70 mg once daily for 6 weeks	Good prognosis
Garibyan and Shaw[34]	2013	United States	1	Male	50	G. adiacens	Bivalvular IE	Mitral and aortic	Initial treatment with vancomycin, switched to penicillin and gentamicin based on antibiotic susceptibility; mitral and aortic valve replacement surgery; post-operative IV penicillin for two weeks	Good prognosis
Halford et al[36]	2019	United States	1	Male	82	G. adiacens	IE with paravalvular abscess and complete heart block	Aortic	Tissue aortic valve replacement, pacemaker placement, and antibiotic regimen of ampicillin and ceftriaxone for 6 weeks	Good prognosis
Sendi et al[42]	2019	Switzerland	1	Female	32	G. adiacens	Cardiac implantable electronic devices-related infection and bioprosthesis endocarditis	Bioprosthetic pulmonary valve	Conservative treatment with penicillin G and gentamicin for 2 weeks, followed by ceftriaxone for 4 weeks, and oral amoxicillin for 6 weeks (total 12 weeks of therapy); no device removal or surgical intervention	Good prognosis
Jeng et al[44]	2005	United States	1	Male	18	G. adiacens	Prosthetic valve IE	Prosthetic pulmonary valve	Vancomycin, gentamicin and rifampin for 6 weeks	Good prognosis
Loganathan et al[29]	2020	United States	1	Female	81	G. adiacens	IE and tubulovillous adenoma of the sigmoid colon	Aortic	Started on vancomycin and discharged home on IV vancomycin for 6 weeks for native valve IE	Good prognosis
García-Granja et al[47]	2019	Spain	5	Male, male, male, male, male	43, 53, 57, 65, 50	G. adiacens, Abiotrophia defective; G. adiacens, Abiotrophia defective; G. adiacens, Abiotrophia defective; G. adiacens, Abiotrophia defective; Abiotrophia defectiva	IE with vegetation; IE with vegetation and periannular complications; IE with vegetation; IE with vegetation, renal failure, and septic shock; IE with vegetation	Aortic native valve; aortic native valve; mitral native valve; mitral native valve; aortic native valve	Elective surgery for severe valvular regurgitation, antibiotic therapy with ceftriaxone and gentamicin for 4 weeks. Urgent surgery due to periannular complications, antibiotic therapy with penicillin and gentamicin for 5 weeks. No surgery required, antibiotic therapy with ampicillin and gentamicin for 4 weeks. Urgent surgery due to heart failure, antibiotic therapy with penicillin, ceftriaxone, and gentamicin for 4 weeks. Urgent surgery due to heart failure, antibiotic therapy with penicillin and gentamicin for 4 weeks	Good prognosis; mortality; good prognosis; mortality due to septic shock; good prognosis

G. adiacens: Granulicatella adiacens; G. elegans: Granulicatella elegans; IE: Infective endocarditis; IV: Intravenous.

OSTEOMYELITIS

G. adiacens is recognized as an infrequently encountered pathogen but is becoming a major possible cause of osteomyelitis and septic arthritis. Of the cases reviewed in detail, vertebral osteomyelitis represented the most frequently noted condition involving a number of spinal levels including, L2-L5, T10/11[13,41,50-53]. The other conditions were septic arthritis[54], mandibular osteomyelitis in a pediatric patient[55], and suprapatellar and elbow abscesses[52]. Several had concomitant infections with IE of native valve or prosthetic origin, and one case even presented with a brain abscess[13,18,41]. Most adult affected patients were males, middle-aged to elderly, with scantier representation of females and only one child.

Clinical manifestations changed according to the site of infection. Common symptoms included backache, swelling of joints, and fever. In case of vertebral involvement, localized tenderness of the spine and difficulty in ambulation were noted[51,52]. In one instance, sacroiliitis due to endocarditis presented atypically with unilateral hip pain and signs of inflammation[12]. Jaw pain, swelling, and difficulty in chewing characterized mandibular osteomyelitis[13,55]. Some of the patients had a history of recent dental work or cardiac surgery, which can increase the chances of the presence of bacteria in the bloodstream[13].

G. adiacens is a fastidious and slow-growing microorganism; diagnosis primarily relied on blood culture, in some cases, detection with conventional methods was completely futile. Successful isolation could be achieved by inoculating synovial fluid into blood cultures and molecular identification in cases that standard cultures could not obtained[54,56]. Magnetic resonance imaging and computed tomography imaging techniques were essential for the detection of osteomyelitis, discitis, and associated abscesses[50,51,53]. Sometimes, in evaluating the information, a bone biopsy or an intraoperative culture was needed to make a conclusive diagnosis[52]. For osteomyelitis, sonication of explanted hardware combined with 16S rRNA polymerase chain reaction enhances detection. A study by York et al[51] highlighted its utility in spinal infections where cultures were negative, enabling targeted antibiotic therapy.

To treat these conditions, prolonged intravenous courses for most patients were common. An array of drugs was used, usually, it was penicillin, gentamicin, and ceftriaxone, vancomycin, and ertapenem[13,41,52]. Drug modification occurred based on susceptibility or side effects; for example, in the mandibular case, the first therapy with linezolid and ciprofloxacin was later replaced[55]. Step-down oral therapy included clindamycin and amoxicillin[57,58]. Wherever there was spinal instability, abscess formation, or a poor antibiotic response, surgery was indicated. The procedures performed were vertebral corpectomy[51], arthroscopic irrigation[54], endoscopic lumbar discectomy[58], and multiple bone curettages. In one case, hyperbaric oxygen therapy was used for chronic mandibular osteomyelitis[11]. Replacement of a valve was needed for those with advanced IE[41].

G. adiacens infections typically respond well to early identification and tailored antimicrobial therapy, with most patients achieving full clinical resolution. Early onset of especially targeted intravenous antibiotics, often combined with some kind of surgery (either drainage, curettage, or possible future surgery stabilization), proved significant to these patients’ positive outcomes. The absence of reported fatalities underscores the effectiveness of timely diagnosis and management in reducing the morbidity of these infections. Therapeutic outcomes were favorable, even in complex clinical scenarios, such as endocarditis, discitis, or brain abscesses. Only 1 patient was lost to follow-up[56] (Table 2).

Table 2 Osteomyelitis.

Ref.	Year	Country	Patients	Sex	Age, years	Granulicatella species	Diagnosis	Intervention	Outcome/prognosis
Rosenthal et al[13]	2002	Germany	1	Male	68	G. adiacens	Vertebral osteomyelitis at the T10/11 Level and IE	Bed rest, antibiotics (penicillin, rifampin, gentamicin), and discontinuation of gentamicin due to resistance	Good prognosis
Hepburn et al[54]	2003	United States	1	Female	68	G. adiacens	Septic arthritis	Arthroscopic irrigation, cefazolin (4 weeks), gentamicin (2 weeks), and synovial fluid inoculation into blood culture bottles for diagnosis	Good prognosis
Fukuda et al[50]	2010	Japan	1	Male	73	G. adiacens	Vertebral osteomyelitis at L3/L4 Level and discitis	penicillin G (20 million U/day) and gentamicin (150 mg/day) for 4 weeks, followed by amoxicillin (1500 mg/day); mitral valvoplasty performed 107 days after treatment initiation	Good prognosis
York et al[51]	2016	Sweden	1	Male	46	G. adiacens	Vertebral osteomyelitis at L2 Level	Lateral corpectomy and posterior fixation for spinal stabilization; antibiotic therapy with vancomycin and ceftazidime, later narrowed to vancomycin for six weeks	Good prognosis
Sandhu et al[52]	2017	United States	1	Male	61	G. adiacens	Vertebral osteomyelitis at L3/4 Level	Ceftriaxone and gentamicin	Good prognosis
Bakhsh et al[53]	2017	United States	1	Male	48	Granulicatella/Abiotrophia species	Vertebral osteomyelitis at L3/4 Level with associated discitis and epidural phlegmon	IV vancomycin for 6 weeks	Good prognosis
Gupta et al[56]	2018	India	2	Male; male	30; 18	G. adiacens; G. adiacens	Suprapatellar abscess; right elbow abscess	Abscess drainage, intravenous cefotaxime, followed by oral cefuroxime; abscess drainage	Good prognosis; patient lost to follow up
Patil et al[41]	2019	United States	1	Female	44	G. adiacens	Vertebral osteomyelitis at L3-L4 Level, native mitral valve IE, and brain abscess	Mitral valve replacement surgery; six weeks of intravenous vancomycin and ertapenem	Good prognosis
Mizuki et al[55]	2019	Japan	1	Female	10	G. adiacens	Chronic mandibular osteomyelitis	Initially, ampicillin/sulbactam; later switched to linezolid and ciprofloxacin due to adverse drug events; multiple curettages of mandibular bone; hyperbaric oxygen therapy	Good prognosis
Van Der Palen et al[57]	2021	Egypt	1	Male	45	G. adiacens	Vertebral osteomyelitis at L2/L3 Level	Intravenous penicillin (6 million U/day for 3 weeks), followed by oral clindamycin (600 mg three times daily for 2 weeks)	Good prognosis
Kuo et al[58]	2020	Taiwan	1	Female	40	G. adiacens	Vertebral osteomyelitis at L5/S1 Level following mitral valve repair	Percutaneous endoscopic interlaminar lumbar discectomy; intravenous vancomycin for 14 days, followed by oral amoxicillin	Good prognosis
Maudlin et al[12]	2022	Australia	1	Male	32	G. adiacens	Subacute IE with right sacroilitis	Six-week course of intravenous ceftriaxone (2 g daily) and two-week course of gentamicin (240 mg daily); no surgical intervention	Good prognosis

G. adiacens: Granulicatella adiacens; IE: Infective endocarditis; IV: Intravenous.

PULMONARY INFECTIONS

Pulmonary infections attributed to Granulicatella species, although infrequent, have been associated with severe clinical outcomes including multifocal pneumonia, empyema, and lung abscess formation[59,60]. These infections often occur in polymicrobial contexts, frequently in conjunction with Streptococcus constellatus[60]. Predisposing factors encompass immunocompromised states, underlying pulmonary pathology, and recent invasive procedures[61]. Among the species, G. adiacens, typically a commensal of the upper respiratory tract, may assume pathogenicity in susceptible hosts, leading to bacteremia, sepsis, and other invasive complications[62]. In patients with hematological malignancies and neutropenia, Granulicatella bacteremia represents a notable clinical concern[61].

Granulicatella species form part of the normal flora of the oral, genital, and GIT tracts but have demonstrated pathogenic potential in immunocompromised individuals, manifesting as endocarditis, septic emboli, necrotizing fasciitis, and pulmonary infections[62-65]. Diagnostic challenges arise due to the organism’s fastidious growth requirements and atypical morphology[64]. Therapeutic regimens generally include prolonged courses of broad-spectrum antimicrobials, such as vancomycin, ampicillin, or gentamicin, though emerging resistance complicates management[63,66]. In cases involving abscesses or complex effusions, procedural interventions may be warranted[59]. Despite aggressive treatment, outcomes may be poor, particularly in patients with significant comorbidities[62,64].

This narrative review compiles reported cases of pulmonary infections associated with Granulicatella species, highlighting clinical characteristics, interventions, and outcomes. The review includes studies from 2014 to 2022 across China, United States, Korea, India, and South Africa, encompassing both male and female patients aged 21 to 68 years. G. adiacens was the predominant species, while G. elegans was identified in one case. Clinical presentations ranged from lung abscesses, empyema, and pneumonia to sepsis and multifocal pulmonary involvement, often in association with other pathogens or comorbidities like bronchogenic carcinoma, tuberculosis, or human immunodeficiency virus. Interventions involved antibiotic therapies, commonly vancomycin, ceftriaxone, and beta-lactams, often combined with surgical drainage or supportive measures. Most cases demonstrated improved clinical status, though one mortality was reported due to acute myocardial infarction. These reports suggest that while Granulicatella species are rare pulmonary pathogens, early microbiological identification and personalized therapeutic strategies generally result in favorable clinical trajectories, underscoring the importance of early microbiological identification and multidisciplinary management (Table 3)[59,60,63,67-69].

Table 3 Pulmonary infections.

Ref.	Year	Country	Patient(s)	Sex	Age, years	Granulicatella species	Diagnosis	Intervention	Outcome/prognosis
Yang et al[59]	2021	China	1	Female	52	G. adiacens (along with Eikenella corrodens and Staphylococcus aureus)	Lung abscess with right-sided hydropneumothorax and bronchogenic carcinoma	Thoracic puncture and drainage, antibiotic therapy with moxifloxacin and ornidazole, and nutritional support	Good prognosis
Freire et al[60]	2022	United States	1	Male	41	G. adiacens and Streptococcus constellatus	Lung abscess with persistent left lower lobe collapse	Augmentin for 4 weeks, followed by IV vancomycin and oral levofloxacin for 6 weeks; segmentectomy scheduled due to persistent lung collapse	Persistence of lung collapse secondary to abscesses
Koh et al[67]	2014	Korea	3	Male; male; male	62; 21; 49	G. adiacens; G. adiacens; G. adiacens	Sepsis; pneumonia; peritonitis and advanced gastric cancer	IV cefotaxime and IV vancomycin; antibiotics (details not given); antibiotics (details not given)	Good prognosis; good prognosis; good prognosis
Purohit et al[68]	2022	India	1	Male	68	G. adiacens	Left sided empyema complicated by sepsis and necrotizing fasciitis	Initially, cefuroxime. Later: Ceftriaxone and linezolid, intercostal chest tube placement for fluid drainage; fasciotomy for necrotizing fasciitis	Mortality due to acute myocardial infarction
Mvelase et al[69]	2016	South Africa	1	Female	30	G. elegans	Thoracic empyema with tuberculosis and human immunodeficiency virus infection	Intercostal drainage of pleural effusion; initially, ceftriaxone. Later switched to penicillin based on susceptibility testing; three weeks of hospitalization	Good prognosis
Acharya et al[63]	2020	United States	1	Male	56	G. adiacens	Right-sided multifocal pneumonia with complex parapneumonic effusion and bacteremia	Chest tube drainage, tissue plasminogen activator and deoxyribonuclease therapy, and antibiotic regimen including vancomycin, piperacillin/tazobactam, ceftriaxone, ampicillin, gentamicin, and metronidazole	Good prognosis

G. adiacens: Granulicatella adiacens; G. elegans: Granulicatella elegans; IV: Intravenous.

GIT INFECTIONS

Although traditionally associated with endocarditis and bacteremia, Granulicatella species have increasingly been implicated in GIT infections. The clinical spectrum includes peritonitis, bacterascites, and intra-abdominal abscesses, such as appendiceal and splenic abscesses[56,70]. These infections often arise in high-risk patients, particularly those with recent abdominal surgery, ventriculoperitoneal shunts, or underlying malignancies[61,71].

Diagnostic evaluation involves ascitic fluid analysis, blood cultures, and imaging modalities. However, the fastidious nature of Granulicatella species complicates detection, often necessitating specialized culture media or molecular diagnostic techniques[71,72]. Management strategies require both source control and targeted antimicrobial therapy. Drainage procedures or surgical intervention are crucial, particularly in cases of abscesses or perforation[70]. Empirical antibiotic regimens commonly include ampicillin, vancomycin, and metronidazole[61,66]. While prognosis is generally favorable with timely intervention, clinical outcomes decline significantly in cases of GIT perforation and septic shock without timely surgical intervention.

Several case reports and series have documented GIT infections caused by Granulicatella species, highlighting a diverse patient population and clinical spectrum. Abdul-Redha et al[73] described three pediatric cases (ages 1.78-4.7 years) with G. elegans-associated intra-abdominal infections ranging from ileus with necrosis to intestinal perforation and abscesses; two recovered, while one succumbed. Koh et al[67] reported three adult male patients (ages 21-62) in Korea with G. adiacens-related infections, including peritonitis in the context of gastric cancer, all of whom had favorable outcomes. Vivar et al[74] described a 13-year-old girl with Granulicatella and Abiotrophia-related peritonitis linked to a ventriculoperitoneal shunt infection, treated successfully with surgery and antibiotics. Similarly, adult patients in the United States were reported with bacterascites[75], ruptured appendicitis with retrocecal abscess[76], and peritonitis with malignant ascites[77], all responding well to drainage and antibiotic therapy. Collectively, these cases underscore the importance of initial identification and intervention (Table 4).

Table 4 Gastrointestinal infections.

Ref.	Year	Country	Patient(s)	Sex	Age, years	Granulicatella species	Diagnosis	Intervention(s)	Outcome/prognosis
Abdul-Redha et al[73]	2007	Denmark	3	Male; female; female	78; 71; 47	G. elegans; G. elegans; G. elegans	Bacteremia with abdominal focus (ileus and necrosis of the ascending colon). Bacteremia with abdominal focus (intestinal perforation and intra-abdominal abscess). Bacteremia with abdominal focus (intra-abdominal abscess)	Right-side hemicolectomy; antibiotics (cefuroxime, metronidazole, ciprofloxacin). Surgery for intestinal perforation and abscess drainage; antibiotics (penicillin, gentamicin, metronidazole, imipenem, amphotericin B). Surgery for intra-abdominal abscess; antibiotics (penicillin, gentamicin, metronidazole, cefuroxime, ciprofloxacin)	Mortality; good prognosis; good prognosis
Koh et al[67]	2014	Korea	3	Male; male; male	62; 21; 49	G. adiacens; G. adiacens; G. adiacens	Sepsis; pneumonia; peritonitis and advanced gastric cancer	IV cefotaxime and IV vancomycin; antibiotics (details not given); antibiotics (details not given)	Good prognosis; good prognosis; good prognosis
Vivar et al[74]	2017	United States	1	Female	13	Granulicatella and Abiotrophia species (not specified)	Peritonitis associated with ventriculoperitoneal shunt and central nervous system infection	Laparoscopic surgery, ventriculoperitoneal shunt externalization, and antibiotic therapy including vancomycin, rifampin, and metronidazole	Good prognosis
Cincotta et al[75]	2015	United States	1	Male	50	G. adiacens	Bacterascites (nonneutrocytic monomicrobial ascites)	Vancomycin	Good prognosis
Shamrock et al[76]	2019	United States	1	Male	5	G. adiacens	Ruptured appendicitis with retrocecal abscess	Abscess drainage, IV antibiotics (vancomycin and meropenem), followed by oral amoxicillin/clavulanate and metronidazole; elective laparoscopic appendectomy performed 3 months later	Good prognosis
Elfessi et al[77]	2019	United States	1	Male	38	G. adiacens	Secondary bacterial peritonitis associated with malignant ascites	Fuid resuscitation, removal of the peritoneal catheter, initial broad-spectrum antibiotics (vancomycin, aztreonam, and metronidazole), later narrowed to vancomycin monotherapy (8 days)	Good prognosis

G. adiacens: Granulicatella adiacens; IV: Intravenous.

SEPTIC SHOCK

Granulicatella species, formerly known as NVS, are increasingly recognized as causative agents of severe invasive infections, including septic shock. Although classically associated with IE, these organisms may lead to septic shock secondary to abscess formation or procedural complications, such as splenic abscess following endoscopic ultrasound-guided fine-needle biopsy[70]. Their fastidious nature complicates early identification; however, advanced diagnostic modalities like MALDI-TOF MS have improved detection rates[78]. Notably, IE caused by Granulicatella can result in serious sequelae including heart failure, systemic embolization, and perivalvular abscesses, with a reported mortality rate of 17%[7].

Management of Granulicatella-associated septic shock necessitates rapid administration of empiric broad-spectrum antibiotics, such as vancomycin or piperacillin-tazobactam, with a preference for monotherapy in the initial phase to avoid drug interactions and toxicity[78,79]. Source control remains the cornerstone of effective management, encompassing interventions like splenectomy, surgical debridement, abscess drainage, and device removal, depending on the infection site[80]. In cases of GIT perforation or obstruction, timely surgical intervention within 6 hours significantly improves survival[81,82].

Prognosis in septic shock is highly contingent on the anatomical source and the speed of intervention. Mortality is highest in ischemic bowel and lowest in obstructive uropathy[83]. Immunocompromised patients with cancer are particularly vulnerable due to multifactorial immunosuppression[84]. Delays in appropriate antimicrobial therapy and inadequate source control markedly increase mortality, emphasizing the critical need for rapid diagnosis, multidisciplinary coordination, and adherence to guideline-based therapy[82,85].

A review of case reports highlights the diverse clinical presentations and outcomes of septic shock and severe sepsis associated with Granulicatella species. Most infections were caused by G. adiacens, with one report involving G. albicans and another Abiotrophia defective, a closely related species. Patient ages ranged from neonates to elderly adults (89 years), with both sexes affected. Sources of infection included splenic abscess post-endoscopic ultrasound-guided fine-needle biopsy[70], trauma-associated sepsis[86], IE with glomerulonephritis[22], post-procedural bacteremia[87,88], and malignancy-related infections[77,89].

Management strategies varied, with common use of vancomycin, cefotaxime, piperacillin-tazobactam, and aminoglycosides. Surgical interventions such as splenectomy and abscess drainage were occasionally required. Patient outcomes were largely positive when source control and effective antimicrobial therapy were implemented without delay, though mortality was reported in patients with underlying malignancy and endocarditis[22,89]. These findings underscore the need for heightened clinical vigilance, early antimicrobial initiation, and individualized management in Granulicatella-associated septic complications (Table 5)[22,67,70,76,77,86-91].

Table 5 Septic shock.

Author	Year	Country	Patients	Sex	Age, years	Granulicatella species	Diagnosis	Intervention	Outcome/prognosis
Cho et al[70]	2021	South Korea	1	Male	45	G. adiacens	Septic shock due to a splenic abscess following endoscopic ultrasound-guided fine needle biopsy of a splenic mass	Initially, IV piperacillin/tazobactam, later switched to ampicillin/sulbactam; splenectomy performed 40 days after septic shock event; subsequent chemotherapy for diffuse large B-cell lymphoma	Good prognosis
Gardenier et al[86]	2011	United States	1	Female	89	G. adiacens	Sepsis due to trauma injuries	Cefazolin	Good prognosis
Shaik et al[22]	2020	United States	1	Male	46	Granulicatella albicans	IE and post-infectious glomerulonephritis	IV vancomycin and immunosuppressive therapy. Later placed on hemodialysis.	Poor prognosis
Datta et al[89]	2018	United States	1	Female	69	G. adiacens	Bacteremia with brain metastases	Single dose of oritavancin after vancomycin therapy	Mortality
Quartermain et al[90]	2013	United Kingdom	1	Male	Neonate	G. adiacens	Neonatal bacteremia	Benzylpenicillin and amikacin for 6 days	Good prognosis
Koh et al[67]	2014	Korea	3	Male, male, male	62; 21; 49	G. adiacens; G. adiacens; G. adiacens	Sepsis; pneumonia; peritonitis and advanced gastric cancer	IV cefotaxime and IV vancomycin; antibiotics (details not given); antibiotics (details not given)	Good prognosis; Good prognosis; Good prognosis
Chen et al[87]	2016	Taiwan	1	Male	81	G. adiacens	Bacteremia following flexible sigmoidoscopy	Initially: Ampicillin/sulbactam and clarithromycin. Later: Ampicillin and gentamicin	Good prognosis
Divoky et al[88]	2014	United States	2	Female, female	38; 47	G. adiacens, Streptococcus agalactiae	Bacteremia complicating endometrial ablation	IV vancomycin, IV ciprofloxacin and IV gentamicin; IV ampicillin, clindamycin and gentamicin	Good prognosis
Lopardo et al[91]	2007	Argentina	1	Male	6	Abiotophia defectivea	Bacteremia in immunocompromised patient	Ceftazidime and amikacin, later changing amikacin to vancomycin, teicoplanin and acyclovir	Good prognosis
Shamrock et al[76]	2019	United States	1	Male	5	G. adiacens	Ruptured appendicitis with retrocecal abscess	Abscess drainage, IV antibiotics (vancomycin and meropenem), followed by oral amoxicillin/clavulanate and metronidazole; elective laparoscopic appendectomy performed 3 months later	Good prognosis
Elfessi et al[77]	2019	United States	1	Male	38	G. adiacens	Secondary bacterial peritonitis associated with malignant ascites	Fuid resuscitation, removal of the peritoneal catheter, initial broad-spectrum antibiotics (vancomycin, aztreonam, and metronidazole), later narrowed to vancomycin monotherapy (8 days)	Good prognosis

G. adiacens: Granulicatella adiacens; IE: Infective endocarditis; IV: Intravenous.

BRAIN ABSCESS

Central nervous system (CNS) infections caused by Granulicatella species, although uncommon, represent a clinically significant complication, often arising secondary to IE, dental procedures, or cranial trauma. These infections, particularly brain abscesses, may follow septic embolization from cardiac valves or hematogenous spread[7,24]. While Granulicatella endocarditis classically involves the mitral or aortic valves and predisposes patients to neurologic sequelae such as infectious cerebral aneurysms, CNS involvement remains underreported and poorly characterized in the literature[24,92].

Accurate diagnosis is critical and relies on neuroimaging modalities such as magnetic resonance imaging or computed tomography, which detect structural lesions, in conjunction with cerebrospinal fluid analysis in cases of suspected meningitis. Owing to the fastidious growth requirements of Granulicatella, traditional culture methods are often inadequate. Advanced molecular diagnostics, including 16S rRNA gene sequencing and NGS, have significantly improved pathogen detection in polymicrobial brain abscesses, identifying both typical organisms such as Streptococcus intermedius and rare pathogens including Granulicatella species[93,94].

Therapeutic strategies include surgical drainage of abscesses combined with prolonged intravenous antimicrobial therapy, typically involving penicillin, vancomycin, or meropenem[66,95]. Prognosis is favorable with timely intervention; however, delayed management increases the risk of neurologic sequelae such as seizures or cognitive impairment[96,97]. Multidisciplinary care remains essential for optimizing clinical outcomes[98].

A review of reported cases highlights the diverse clinical presentations and management strategies associated with Granulicatella species-related brain abscesses and CNS infections. Across studies from various geographic regions, patients ranged from pediatric to elderly, with a slight predominance of female cases. In most reports, G. adiacens was the predominant isolate, although mixed infections with Fusobacterium and Abiotrophia species were also observed[99,100]. Common risk factors included IE, neurosurgical procedures, dental interventions, and septic embolization[41,92]. Diagnosis was primarily established through clinical imaging and microbiological confirmation, with molecular diagnostics employed in complex cases. Treatment regimens included prolonged intravenous antibiotic therapy, commonly penicillin, vancomycin, or meropenem, often combined with surgical drainage or valve repair when indicated. Most patients experienced full neurological recovery following early diagnosis and coordinated intervention, although mortality was reported in cases with advanced metastatic disease or delayed therapy[89]. These findings underscore the importance of timely recognition, individualized antimicrobial strategies, and multidisciplinary management in achieving optimal outcomes (Table 6).

Table 6 Brain abscess.

Ref.	Year	Country	Patients	Sex	Granulicatella species	Diagnosis	Intervention	Outcome/prognosis
Datta et al[89]	2018	United States	1	Female	G. adiacens	Bacteremia with brain metastases	Single dose of oritavancin after vancomycin therapy	Mortality
Patil et al[41]	2019	United Kingdom	1	Female	G. adiacens	IE with ruptured chordae tendinae, septic embolization, brain abscess and lumbar spine osteomyelitis	IV vancomycin and meropenem. Mitral valve replacement with Hancock type 2 mitral valve tissue. Six-week course of intravenous vancomycin and ertapenem	Good prognosis
Cerceo et al[99]	2004	United States	2	Female; female	G. adiacens; Abiotrophia defectiva	Epidural abscess with meningitis. Brain abscess with meningitis	Surgical drainage of epidural abscess; antibiotic therapy with penicillin and gentamicin; vancomycin and gentamicin	Good prognosis; good prognosis
Yeung[92]	2021	Canada	1	Female	G. adiacens	Central nervous system infection following suboccipital craniotomy for grade 1 pilocytic astrocytom	Initially, penicillin G and gentamicin; later switched to meropenem due to resistance; finally transitioned to vancomycin; total of 30 days of effective antimicrobial therapy	Good prognosis
Chang et al[30]	2008	Taiwan	1	Male	G. adiacens	IE with infectious intracranial aneurysms and recurrent hemorrhagic stroke	Initially, ampicillin/sulbactam for 14 days, followed by oral amoxicillin/clavulanic acid for 2 weeks. Surgical clipping of intracranial aneurysms. Parenteral oxacillin and gentamicin therapy for recurrent infectious intracranial aneurysms. Mitral valvuloplasty performed 5 months after stabilization of neurological function	Symptom resolution with no further brain insults over a 5 year follow up period
Culleton et al[37]	2016	Ireland	1	Male	G. adiacens	IE with embolic stroke and splenic artery aneurysms	Mitral and aortic valve repair surgery, followed by emergency splenectomy	Good prognosis
Akyol et al[100]	2018	Turkey	1	Male	G. elegans, Fusobacterium necrophorum, Peptoniphilus asaccharolyticus	Brain abscess in the right temporal region following tooth extraction	Abscess drainage, empirical antibiotic therapy with ceftriaxone and metronidazole, later switched to penicillin, and subsequently to linezolid due to penicillin allergy; total of 10 weeks of antibiotic treatment	Good prognosis
Vivar et al[74]	2017	United States	1	Female	Granulicatella species; Abiotrophia species; (not specified)	Peritonitis associated with ventriculoperitoneal shunt and central nervous system infection	Laparoscopic surgery, ventriculoperitoneal shunt externalization, and antibiotic therapy including vancomycin, rifampin, and metronidazole	Good prognosis
Opperman et al[38]	2020	South Africa	1	Female	G. adiacens	IE with stroke and mycotic aneurysm	IV penicillin for 4 weeks and gentamycin for 2 weeks	Good prognosis

G. adiacens: Granulicatella adiacens; G. elegans: Granulicatella elegans; IE: Infective endocarditis; IV: Intravenous.

IMPLANT INFECTIONS

Granulicatella species, particularly G. adiacens, have increasingly been implicated in implant-associated infections, encompassing a wide spectrum including prosthetic heart valves, orthopedic prostheses, cardiac implantable electronic devices, and breast implants[32,42,101,102]. These infections are characteristically indolent and frequently underdiagnosed due to the organism’s fastidious growth requirements and resultant culture negativity[32,102]. Moreover, Granulicatella demonstrates a marked propensity for biofilm formation, particularly on prosthetic material, which complicates eradication and contributes to persistent or relapsing infection[42,103].

Diagnosis often necessitates the use of advanced microbiological techniques, such as sonication of explanted devices and molecular assays including 16S rRNA gene sequencing or MALDI-TOF MS, which have proven instrumental in identifying these elusive pathogens[104,105]. Imaging modalities support the localization of infection, while intraoperative sampling enhances diagnostic yield.

Therapeutic management mandates a multidisciplinary approach combining prolonged antimicrobial therapy with surgical intervention. Empiric and targeted regimens often incorporate beta-lactams (e.g., penicillin, amoxicillin) and aminoglycosides, although adjunctive use of rifampin is increasingly favored for its biofilm-penetrating properties in prosthetic joint infections[103,104]. Surgical strategies range from debridement to complete device explanation, with the latter associated with superior outcomes and reduced relapse risk[105,106].

Despite aggressive treatment, Granulicatella implant infections are associated with higher relapse rates and treatment failure compared to other streptococcal infections, particularly when foreign material is retained[32]. Long-term follow-up and coordinated care between surgeons, infectious disease specialists, and microbiologists are essential to optimize clinical outcomes and mitigate recurrence[106].

A review of the literature reveals multiple case reports documenting implant-associated infections caused by G. adiacens, affecting a wide range of prosthetic devices. These include prosthetic heart valves[11,45,47], orthopedic implants such as hip and knee prostheses[102,107-111], breast implants[101], cardiac implantable electronic devices[43], and aortic endografts[112]. Infections often followed dental or invasive procedures and presented with delayed symptoms. Diagnosis frequently required culture and imaging, with some cases necessitating sonication of explanted devices. Most patients were treated with prolonged intravenous antibiotics, often involving penicillin, vancomycin, gentamicin, or rifampin. Surgical intervention, ranging from debridement to full prosthesis removal and reimplantation, was common. While clinical recovery was achieved in many cases, recurrence was more likely when infected prosthetic material was not fully explanted (Table 7).

Table 7 Implant infections.

Ref.	Year	Country	Patient(s)	Sex	Age, years	Granulicatella species	Diagnosis	Intervention	Outcomes/prognosis
Jones et al[11]	2018	Georgia	1	Male	70	G. adiacens	Prosthetic valve IE	Initially, piperacillin/tazobactam 3.375 g IV every 6 hours, levofloxacin 500 mg IV every 24 hours. Then modified to vancomycin 15 mg/kg IV every 12 hours, ampicillin 2 g IV every 4 hours. Finally, vancomycin continued and ceftriaxone 2 g IV every 12 hours (substituted for ampicillin)	Good prognosis
del Pozo et al[101]	2008	Spain	1	Female	32	G. adiacens	Bilateral breast implant associated infection	Initially, clindamycin and levofloxacin; later switched to a combination of rifampin and amoxicillin for 4 months after relapse	Good prognosis
Warren et al[47]	2023	United States	1	Female	74	G. adiacens	Recurrent IE of a bioprosthetic aortic valve	Initial treatment with intravenous ceftriaxone for six weeks; later re-operative aortic valve repair with modified nicks root enlargement; subsequent treatment with intravenous gentamicin and vancomycin for six weeks	Good prognosis
Aweid et al[107]	2016	United Kingdom	1	Male	81	G. adiacens	Prosthetic hip joint infection following dental treatment	Surgical washout and debridement, followed by a combination of antibiotics (including benzylpenicillin, flucloxacillin, vancomycin, and others)	Mortality due to community acquired pneumonia
Badrick et al[102]	2021	Australia	1	Male	79	G. adiacens	Prosthetic hip infection following dental treatment	Two-stage revision total hip arthroplasty with antibiotic-impregnated cement spacer and six weeks of intravenous benzyl penicillin	Good prognosis
Pingili et al[108]	2017	United States	1	Male	64	G. adiacens	Prosthetic knee infection following dental treatment	Resection of the infected knee arthroplasty, placement of antibiotic cement spacer, and IV ertapenem for 6 weeks; followed by revision total knee arthroplasty	Good prognosis
Riede et al[109]	2004	Switzerland	1	Male	43	G. adiacens	Prosthetic knee associated infection	Implantation of gentamicin loaded cement spacer with IV amoxicillin and amikacin, reimplantation surgery of knee with IV amoxicillin, amikacin and oral rifampin contineud	Good prognosis
Quiroga et al[23]	2012	Spain	1	Male	86	G. adiacens	IE with associated glomerulopathy	IV daptomycin (10 mg/kg/48 hours), later switched to ceftriaxone; tooth extraction; no surgical intervention due to age and comorbidities	God prognosis
Plate et al[112]	2018	Switzerland	1	Male	60	G. adiacens	Aortic endograft infection	Combination therapy clarithromycin, rifabutin, ethambutol and amikacin. Later, amikacin replaced by moxifloxacin	Good prognosis
Sendi et al[42]	2019	Switzerland	1	Female	32	G. adiacens	Cardiac implantable electronic devices-related infection and bioprosthesis endocarditis	Conservative treatment with penicillin G and gentamicin for 2 weeks, followed by ceftriaxone for 4 weeks, and oral amoxicillin for 6 weeks (total 12 weeks of therapy); no device removal or surgical intervention	Good prognosis
Mougari et al[110]	2016	France	1	Male	55	G. adiacens	Prosthetic knee arthritis following dental treatment	Two-step surgery involving prosthesis removal, synovectomy, and curettage; placement of a spacer; antimicrobial therapy with amoxicillin and rifampicin for three months; reimplantation of a total knee prosthesis	Good prognosis
Narayana Murthy et al[111]	2021	United Kingdom	1	Male	65	G. adiacens	Prosthetic knee joint infection following acupuncture treatment	Initial treatment with IV vancomycin, followed by six weeks of IV clindamycin (450 mg four times daily); additional open debridement surgery to reduce bacterial load	Good prognosis
Jeng et al[44]	2005	United States	1	Male	18	G. adiacens	Prosthetic valve IE	Vancomycin, gentamicin and rifampin for 6 weeks.	Good prognosis

G. adiacens: Granulicatella adiacens; IE: Infective endocarditis; IV: Intravenous.

URINARY TRACT AND EYE INFECTIONS

G. adiacens, a nutritionally variant streptococcus, has been identified as a rare pathogen in urinary and ocular infections. Although UTIs involving G. adiacens are infrequent, they have been documented in cases of native vertebral osteomyelitis secondary to urethral involvement and in peritonitis associated with CAPD[56]. These infections are often underdiagnosed due to the organism’s fastidious nature, necessitating enriched culture media and molecular diagnostic approaches for accurate identification[113]. β-lactams and glycopeptides, including amoxicillin and vancomycin, remain the cornerstone of treatment, with extended courses often required for deep-seated infections like native vertebral osteomyelitis[114]. Increasing resistance to penicillin has prompted a shift toward empirical glycopeptide use in recent reports.

Ocular infections caused by Granulicatella species., though rare, are clinically significant and include keratitis and postoperative endophthalmitis[115]. These typically follow ocular surgery or trauma and are more likely in immunocompromised patients, particularly those on corticosteroid therapy. Despite Gram-negative organisms being predominant in global endophthalmitis cases, Granulicatella remains an important Gram-positive pathogen[116]. Management involves intravitreal antibiotics, vancomycin for Gram-positive coverage and ceftazidime for Gram-negative coverage, with vitrectomy indicated in severe cases. Outcomes vary; although early, aggressive therapy can preserve vision, delayed treatment may necessitate enucleation or evisceration[117].

A limited number of case reports have documented Granulicatella species as causative agents in urinary tract and ocular infections, highlighting their diverse clinical manifestations and management approaches. In urinary infections, G. adiacens was identified in a 63-year-old male with urethritis via Gram-stained urethral swabs and culture on chocolate agar[118]. Lopardo et al[91] reported two pediatric cases, one with UTI and another with sinusitis, successfully treated with amoxicillin and ciprofloxacin-based regimens, although 1 patient succumbed due to relapsed leukemia (Table 8).

Table 8 Urinary tract infections.

Ref.	Year	Country	Patient(s)	Sex	Age, years	Granulicatella species	Diagnosis	Intervention	Outcomes/prognosis
Arora et al[118]	2016	India	1	Male	63	G. adiacens	Urethritis	Diagnosis involved urethral swabs, Gram-staining, and culture on chocolate agar to identify the causative pathogen	Not explicitly mentioned
Lopardo et al[91]	2007	Argentina	2	Male; female	12; 4	G. adiacens	UTI; maxillary sinusitis	Amoxicillin; initially, oral ceftriaxone. Later, ciprofloxacin and trimethoprim-sulfamethoxazole	Good prognosis; mortality due to relapse of ALL

G. adiacens: Granulicatella adiacens; UTI: Urinary tract infections; ALL: Acute lymphoblastic leukemia.

Ocular infections showed varied presentations, including dacryocystitis[119], microbial keratitis and endophthalmitis[115], and postoperative endophthalmitis[120]. Most cases followed ocular trauma or surgical interventions. Management included surgical drainage or vitrectomy, combined with topical, systemic, and intravitreal antibiotics such as vancomycin, ceftazidime, and levofloxacin. Prognosis was generally favorable with timely, multidisciplinary intervention (Table 9)[115,119,120-123].

Table 9 Eye infections.

Ref.	Year	Country	Patient(s)	Sex	Age, years	Granulicatella species	Diagnosis	Intervention	Outcomes/prognosis
Ku et al[119]	2015	United States	1	Female	46	G. adiacens	Chronic dacryocystitis	External dacryocystorhinostomy with Crawford stent placement; postoperative antibiotics included oral cephalexin, erythromycin ointment, and tobramycin-dexamethasone drops	Good prognosis
Kim et al[121]	2016	South Korea	1	Male	35	G. elegans	Periorbital infection of the eyelid following dental treatment	Initial treatment with oral amoxicillin/clavulanate for 1 week; recurrence treated with surgical drainage and a 6-week course of oral amoxicillin	Good prognosis
Al-Lozi et al[115]	2022	United States	2	Female; female	24; 65	G. adiacens; G. adiacens	Microbial keratitis with a history of herpes simplex virus type 1 and candida parapsilosis keratitis; microbial keratitis with associated endophthalmitis following penetrating keratoplasty	Topical vancomycin and oral valacyclovir. Intravitreal vancomycin, amikacin, voriconazole, and surgical interventions including keratoprosthesis and pars plana vitrectomy	Good prognosis; good prognosis
Teo et al[122]	2011	Singapore	1	Male	40	G. adiacens	Orbital abscess secondary to a retained wooden foreign body after trauma	Surgical exploration, drainage of the abscess, removal of the wooden foreign body, and a 6-week course of oral levofloxacin following initial intravenous antibiotics	Good prognosis
Steinmetz et al[123]	2021	United States	2	Female; male	74; 88	G. adiacens; Abiotrophia defectiva	1.Endophthalmitis following intravitreal anti-VEGF injection 2.Endophthalmitis following intravitreal anti-VEGF injection	Vitreous tap and injection of intravitreal vancomycin, ceftazidime, and triamcinolone acetonide; followed by pars plana vitrectomy. Vitreous tap and injection of intravitreal vancomycin and ceftazidime; followed by pars plana vitrectomy	Good prognosis; good prognosis; good prognosis
Ishino et al[120]	2022	Japan	1	Female	55	G. adiacens	Postoperative acute infectious endophthalmitis following cataract surgery	Vitrectomy, intraocular lens extraction, silicone oil tamponade, and administration of antibiotics (vancomycin, ceftazidime, levofloxacin, cefmenoxime, and imipenem)	Good prognosis

G. adiacens: Granulicatella adiacens; G. elegans: Granulicatella elegans.

MISCELLANEOUS INFECTIONS

G. adiacens has increasingly been associated with rare and anatomically diverse infections beyond its classical manifestations. Notably, cases involving internal jugular vein thrombosis[124], lingual abscess formation, and tubo-ovarian abscesses underscore the pathogen’s potential for deep-seated, suppurative disease. These infections often arise in the context of mucosal barrier disruption or polymicrobial synergy, particularly within the oral and genitourinary tracts where G. adiacens is a commensal organism. Its fastidious nature poses diagnostic challenges, frequently necessitating enriched culture media or molecular identification techniques for accurate detection[56]. Clinically, these rare presentations may mimic more common etiologies, leading to delayed or missed diagnosis. Optimal management includes both surgical drainage, when indicated, and prolonged, targeted antimicrobial therapy based on susceptibility profiles. These cases highlight the pathogenic versatility of Granulicatella species and the importance of considering them in the differential diagnosis of unusual, deep-tissue infections[125].

Several rare but clinically significant infections caused by Granulicatella species have been reported, underscoring the organism’s potential for diverse pathological presentations. Kawai et al[124] described a case of septic internal jugular vein thrombosis with pulmonary embolism and abscesses, managed successfully with antibiotics and anticoagulation. Stofferahn et al[126] reported a lingual abscess requiring aspiration and dual antibiotic therapy. Altay et al[127] highlighted a peritonitis episode in a patient with CAPD treated with cefazolin and gentamicin. Gensheimer et al[128] documented a tubo-ovarian abscess in a virginal adolescent, necessitating surgical intervention and broad-spectrum antibiotics. All cases reported clinically satisfactory responses (Table 10).

Table 10 Miscellaneous infections.

Ref.	Year	Country	Patient(s)	Sex	Age, years	Granulicatella species	Diagnosis	Intervention	Outcomes/prognosis
Kawai and Shiojiri[124]	2021	Japan	1	Male	58	G. adiacens	Septic internal jugular vein thrombosis with pulmonary embolism and intramuscular abscesses, associated with poor oral hygiene	Long-term antibiotics (initially ampicillin, then cefotaxime, and later oral amoxicillin) and drainage of abscesses; anticoagulation therapy (edoxaban) was initiated to manage thrombosis	Good prognosis
Stofferahn et al[126]	2011	United States	1	Male	52	G. adiacens	Lingual abscess	Initially, ampicillin/sulbactum and linezolid with therapeutic needle aspiration of the lesion. Later, amoxicillin/clavulanate monotherapy.	Good prognosis
Altay et al[127]	2008	Turkey	1	Female	55	G. adiacens	Peritonitis on continuous ambulatory peritoneal dialysis	Cefazolin and gentamicin for 14 days	Good prognosis
Gensheimer et al[128]	2010	United States	1	Female	20	Abiotrophia/Granulicatella	Tubo-ovarian abscess in a virginal adolescent female	Diagnostic laparoscopy and exploratory laparotomy; right salpingo-oophorectomy; antibiotic therapy with piperacillin/tazobactam and metronidazole	Good prognosis

G. adiacens: Granulicatella adiacens.

CONCLUSION

Granulicatella and Abiotrophia species, although rare, are significant pathogens capable of causing severe systemic infections, most notably IE. The nonspecific clinical presentations and the fastidious growth requirements of these organisms often lead to diagnostic delays and therapeutic challenges. This narrative review highlights the diversity of clinical manifestations, diagnostic approaches, and treatment strategies associated with these infections. Clinicians should maintain a high index of suspicion for these pathogens in culture-negative IE and other systemic infections, especially when typical organisms are not isolated. Prompt use of molecular diagnostic techniques and early initiation of targeted antibiotic therapy are crucial for favorable outcomes. Based on the reviewed evidence, we recommend prolonged antibiotic regimens tailored to susceptibility profiles and close multidisciplinary follow-up in cases involving endocarditis or deep-seated infections. Future studies are warranted to establish standardized treatment protocols. Our review thus bridges a critical gap and can inform early diagnosis and optimized management in clinical settings.