Endophthalmitis caused by Enterococcus casseliflavus: a systematic review of literature

Abstract

Introduction

Enterococcus casseliflavus is a rare pathogen in human infections, despite being widely distributed in natural environments. This systematic review aims to evaluate the evidence related to endophthalmitis caused by E. casseliflavus.

Methods

A thorough search of PubMed, PubMed Central, and Scopus databases was conducted, covering the period up to October 2022.

Results

A total of 53 records were identified, with 8 studies reporting a total of 21 cases meeting the inclusion criteria. Among these studies, 7 described isolated case reports, while 1 study described 14 cases. The overall quality of the reports was good, as all articles were determined to have low risk of bias. Vancomycin susceptibility was reported in only one case of isolated case reports, while the remaining cases were all vancomycin resistant. With regard to management, in most cases intravenous ampicillin and linezolid were administered, while only one study reported administration of vancomycin.

Conclusions

Ophthalmologists should be aware of the potential for E. casseliflavus to cause endophthalmitis infections and the challenges associated with its intrinsic resistance to vancomycin.

Introduction

Enterococci cause serious infections, including urinary tract and intra-abdominal infections, bacteremia, endocarditis, as well as meningitis.¹ Enterococcus casseliflavus, a motile member of the Enterococcus species, was first described in 1968 by Mundt and Graham in samples obtained by a variety of plants.² E. casseliflavus has emerged as a species that frequently exhibits resistance to vancomycin and is mostly reported in chronically ill and immunosuppressed patients.³

Indeed, among Enterococcus strains, E. casseliflavus stands out as a rare vancomycin-resistant variant not belonging to the faecium or faecalis groups.³ This strain is widespread in nature, inhabiting soil, animals, and plants. While it typically benignly colonizes the human gastrointestinal tract, it can infrequently cause clinically significant infections in immunocompromised patients. Notably, the biliary tract is the usual entry route for those infections.

Endophthalmitis is considered a rare presentation.¹ Indeed, endogenous endophthalmitis, a rare and potentially sight-threatening ocular infection, arises through hematogenous spread from a distant primary source. Well-defined risk factors include immunosuppression, intravenous drug abuse, and invasive medical procedures.⁴

The occurrence of endophthalmitis varies across different clinical settings, with the most common instances being acute-onset cases following cataract surgery, delayed-onset bleb-related endophthalmitis, and episodes of trauma.⁴ In the context of postoperative endophthalmitis, enterococci were responsible for 2.2% of culture-confirmed cases after cataract surgery or secondary to intraocular lens implantation, as reported in the Endophthalmitis Vitrectomy Study.⁴ Despite appropriate intervention, Enterococcus endophthalmitis often leads to a poor visual outcome. The rising resistance of Enterococcus infections to commonly used antibiotics is currently a cause for concern.³

Herein, we systematically assess through a literature search all the relevant evidence regarding E. casseliflavus endophthalmitis infections.

Methods

Study design

The aim of this systematic review is to comprehensively assess and enhance our understanding of the pathogenic potential of this uncommon microorganism. We therefore performed a qualitative synthesis of published articles reporting endophthalmitis infection from E. casseliflavus in humans.

Search strategy

An extensive bibliographic search of PubMed, PubMed Central and Scopus databases was conducted from inception until the 23^rd of October 2022. No language restriction was applied. The search terms used were: “Enterococcus casseliflavus” AND “Endophthalmitis” and the search was expanded by investigating all the references presented separately.

Eligibility criteria and data extraction

Eligibility criteria for this systematic review included articles reporting at least one case of E. casseliflavus-induced endophthalmitis in humans. Studies that met these inclusion criteria were independently reviewed by two investigators (SAK and APA), with study characteristics being extracted. In the event of any discrepancies between the two investigators, a consensus was reached through discussion and agreement. Data extraction was performed with adherence to the 2020 Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA).⁵ Due to the study design, no institutional review board (IRB) approval was obtained.

Risk of bias assessment

Risk-of-bias assessment was performed independently by 2 reviewers (SAK, APA); disagreements were resolved by consensus. We used the Joanna Briggs Institute (JBI) critical appraisal checklist for case reports.⁶ Each of the studies was assessed according to the following items: patient demographic characteristics, history, current clinical condition, diagnostic tests or assessment methods and their results, the intervention(s) or treatment procedure(s), post-intervention clinical condition, adverse events (harms) or unanticipated events, takeaway lessons. In line with the JBI tool for assessing case reports, a judgment of “yes” indicated low risk of bias, while a judgement of “no” to any of the included questions negatively impacted the overall quality of the case report. Labelling an item as “unclear” indicated an unclear or unknown risk of bias.

Results

Study selection

In Figure 1, the PRISMA flow chart reveals the selection process of included studies. With the above-mentioned search terms, we identified 9 records on Medline via PubMed, 35 records on PubMed Central and 9 records on Scopus. After removing duplicates, 40 articles remained, among which 31 were initially excluded because of study design. Subsequently, we examined in detail the remaining 9 articles. Among them, one study was excluded as it did not meet selection criteria (not reporting a case).¹ Finally, our systematic review included 8 studies with a total of 21 cases (patients with E. casseliflavus endophthalmitis).^7-14

Figure 1. PRISMA flow diagram of articles related to Enterococcus casseliflavus endophthalmitis case reports.

Study characteristics

All included studies were written in English and were published between 2009 and 2021 (Table 1). Seven studies described isolated case reports.^7,8,10-14 while one study described 14 cases.⁹ The latter were reported in India. Regarding the isolated case reports, 2 were from the USA, while the remaining 5 cases were each reported in Canada, Singapore, UK, China, and India, respectively. In the isolated cases, the mean patient age was 28 years old (4-54 years) and all of them were male. In most cases, injury preceded the infection. As far as the case series study is concerned, the mean patient age was 33 years old.

Table 1. Study (case reports) characteristics of Enterococcus casseliflavus endophthalmitis infections reported in the literature.

Author	Year	Study design	Country	Patient age and sex	Cause of Injury	VRE	Treatment	Outcome
Bao7	2019	Case report	China	43 y/o male	Pig’s tail	Yes	Intravitreal vancomycin 1 mg/0.1 mL and ceftazidime 2 mg/0.1 mL, plus intravenous cefuroxime sodium 2500 mg and dexamethasone 10 mg. After antibiogram was available: ampicillin IV 2g/4h and dexamethasone 600 mg/d for 2 weeks	On postoperative day 14, visual acuity in the left eye improved to hand movement. At 6 months post-injury, visual acuity improved to 20/667 (aphakic correction), but optic atrophy occurred
Berenger8	2015	Case report	Canada	4 y/o male	Water stream trauma from a toy water gun	Yes	Vitrectomy, intravitreal ampicillin (50 mg) and amikacin (400 mg), intravenous ampicillin (300 mg/kg/day every 6 h) and linezolid (30 mg/kg/day every 8 h) for 14 days	Over time, the vitreous cavity and anterior segment cleared, and vision improved to 20/400 at seven weeks, 20/400 at 17 weeks and 20/70 at 16 months post-incident
Dave*9	2020	Case series	India	14/29 patients (24 males), mean age 33 y/o	Trauma or endogenous	No	Topical antibiotics and corticosteroid along with oral antibiotics for a period of 1 week	NA
Khurana10	2009	Case report	USA	37 y/o male	Horse’s tail	Yes	Vitrectomy with injection of vancomycin hydrochloride (1 mg/0.1 mL) and ceftazidime (2 mg/0.1 mL), ampicillin	The patient’s pain and anterior segment inflammation resolved 1 week after surgery. Three weeks postoperatively, his visual acuity was hand motions OS. His last visual acuity was light perception OS
Low11	2015	Case report	Singapore	54 y/o male	Metal chip during hammering	Yes	Phacoemulsification, vitrectomy, intravitreal vancomycin (1 mg/0.1 mL) and ceftazidime (2.25 mg/0.1 mL). 6 weeks of intravenous amoxicillin, linezolid, and gentamicin (19 days), followed by oral amoxicillin	At postoperative month 2, visual acuity in his left eye improved to 6/90
Nguyen12	2017	Case report	USA	9 y/o male	Object projected from a lawn mower	Yes	Vitrectomy with oral linezolid 600 mg twice daily for 10 days followed by second vitrectomy with intravitreal amikacin 400 mg 18 days after the initial injury	Visual acuity improved to 20/125 OS. After phacoemulsification with IOL placement 2 months later, vision improved to 20/40 OS and remained stable for 1 year
Sambhav13	2011	Case report	India	20 y/o male	Chronic sinusitis	No	Vitrectomy, intravitreal vancomycin (1 mg in 0.1 mL) and ceftazidime (2.25 mg in 0.1 mL), oral ciprofloxacin 750 mg twice a day followed by topical gentamicin 1 hourly	Recurrent endophthalmitis at 45 days and the patient underwent second vitrectomy with intravitreal vancomycin (1 mg in 0.1 mL) and was started on topical fortified vancomycin and gentamicin along with topical steroids. At the final follow-up visit, 3 months after the last intravitreal injection, the patient had a best corrected visual acuity of 20/60
Stephens14	2021	Case report	UK	Middle-aged male	Open tibial fracture	Yes	Initially intravitreal vancomycin and ceftazidime, pars plana vitrectomy, Intravenous piperacillin-tazobactam and oral linezolid. Discharged with oral amoxicillin and oral linezolid for 6 weeks followed by second pars plana vitrectomy, phacoemulsification and removal of silicon oil.	Permanent monocular blindness

^*Details are given for all 29 patients with enterococcal endophthalmitis [E. casseliflavus (14), E. faecalis (9), E gallinarum (4), E. faecium (1), and E. hirae (1)]. All 14 E. casseliflavus patients were susceptible to vancomycin. NA – not available; OS – “oculus sinister” (left eye); IOL – intraocular lens.

Among all isolated case reports, susceptibility to vancomycin was reported only in one case,¹³ while the rest of the isolated case reports all reported vancomycin resistance. In the case series study, all 14 isolated strains of E. casseliflavus were reported as susceptible to vancomycin by using the Kirby Bauer disc diffusion method.⁹ With regard to management, in most cases intravenous ampicillin and linezolid were administered, while only one study reported administration of vancomycin.⁸

Quality appraisal

The overall quality of the cases was good, as all articles were determined to have low risk of bias. These results are included in Table 2.

Table 2. Reported cases of E. casseliflavus and their risk of bias according to the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports⁶.

Author	Year	Were patient’s demographic characteristics clearly described?	Was the patient’s history clearly described and presented as a timeline?	Was the current clinical condition of the patient on presentation clearly described?	Were diagnostic tests or assessment methods and the results clearly described?	Were the intervention(s) or treatment procedure(s) clearly described?	Was the post-intervention clinical condition clearly described?	Were adverse events (harms) or unanticipated events identified and described?	Does the case report provide takeaway lessons?	Risk of bias
Bao7	2019	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Low
Berenger8	2015	Yes	No	Yes	Yes	Yes	Yes	No	Yes	Low
Dave9	2020	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Low
Khurana10	2009	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Low
Low11	2015	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Low
Nguyen12	2017	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Low
Sambhav13	2011	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Low
Stephens14	2021	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low

Discussion

This systematic review aimed to comprehensively evaluate the existing literature on endophthalmitis infections in humans, caused by E. casseliflavus. To our knowledge, this is the first systematic review conducted on this uncommon microorganism as a causative agent of ocular infections.

E. casseliflavus has been isolated from vegetables and farm animals,^15-17 and can also colonize the gastrointestinal tract of both non-hospitalized and hospitalized individuals.^18,19 It rarely causes invasive infections in humans, mainly in patients with serious comorbidities, such as receipt of organ transplant, hematologic malignancy, diabetes mellitus, renal failure, and immunosuppressive treatment.^20-22 However, the clinical epidemiology of E. casseliflavus is largely unknown due to limitations in microbiological detection and identification.²³

There are several pathogenic determinants that enhance Enterococcus spp. colonizing ability and virulence in humans, thus increasing its ability to cause disease. These determinants are associated with surface proteins, capsule formation, secreted proteins and peptides, aggregation substances, and biofilm formation.^24,25 However, significant interspecies differences have been observed regarding the pathogenic potential of enterococci. In general, E. casseliflavus is considered less virulent than E. faecium and E. faecalis and is associated with lower mortality rates.^3,26

Microbiological confirmation of the clinical diagnosis of infectious endophthalmitis in general is crucial, not only for the identification of the pathogenic microorganism but also to appropriately guide treatment based on isolated species and susceptibility profile. The use of standard culture methods has a low yield, with false negative results up to 30%.²⁷ Many factors contribute to this low rate, such as the sample type, the low concentration of the microbe, or the use of antibiotics before specimen collection.

Typically, cultured samples are aqueous humor or vitreous humor, collected via needle aspiration or posterior vitrectomy. In order to increase sensitivity, automated identification methods, such as matrix-assisted laser desorption/ionization time of flight (MALDI-TOF), and new molecular techniques, such as polymerase chain reaction (PCR) and sequencing, are combined in addition to conventional microbiological diagnostics (direct microscopy, Gram stain, and culture on growth media).

Combining conventional methods with PCR, especially multiplex or panbacterial, and sequencing, can improve sensitivity by 20% to up to 50%, respectively.^28,29 Use of MALDI-TOF can also decrease time to identification up to 24 hours, providing valuable and accurate information earlier and with low cost.³⁰ Furthermore, conventional microbiological methods may underestimate the burden and clinical impact of E. casseliflavus, which is intrinsically resistant to several antibiotics, including vancomycin.³¹ Regarding vancomycin, E. casseliflavus should be always reported as resistant. Misidentification of E. casseliflavus or reporting it as vancomycin-susceptible may lead to empirical treatment failure and worse patient outcomes.

E. casseliflavus resistance to vancomycin is non-transferable and low-level, denoted as VanC phenotype.³¹ This phenotype is derived from a chromosomal cluster of genes encoding a modified pathway of the peptidoglycan biosynthesis, which may be inducible or constitutive. It leads to replacement of the terminal D-Ala of peptidoglycan precursors with D-Ser, which decreases the binding affinity of vancomycin to these precursors, thus blocking its antimicrobial mechanism of action.³² While enterococci possessing the VanC phenotype are considered in vitro susceptible to teicoplanin,³² and may also be considered susceptible to telavancin, oritavancin and dalbavancin,³³ limited data exist regarding the in vivo susceptibility of E. casseliflavus against these antibiotics, thus avoiding them may be prudent. Linezolid, daptomycin and the synergistic combination of anti-enterococcal beta-lactam with aminoglycoside whenever feasible and based on susceptibility results, are among the treatment options for severe infections by E. casseliflavus.¹

The optimal therapeutic approach and the prognosis are difficult to determine due to the low number of endophthalmitis cases caused by E. casseliflavus. The main surgical outcome remains retention of the globe. Concerning visual acuity, the role of early vitrectomy in combination with guided antimicrobial treatment remains crucial.

In the retrospective study by Dave et al., improvement in visual acuity was evident in 34.8% of cases that were managed urgently with vitrectomy and intravitreal treatment (vancomycin + ceftazidime ± dexamethasone).⁹ Interestingly, in this study, E. casseliflavus was reported to be susceptible to vancomycin. Although intravitreal vancomycin remains standard protocol in cases of endophthalmitis, in the majority of the studies included in our systematic review, E. casseliflavus was resistant to vancomycin, which could explain observed differences in outcomes.^34,35 It could also be suggested that in injuries inflicted by animals, where there is high risk of E. casseliflavus-related endophthalmitis, an alternative antibiotic intravitreal regimen that covers E. casseliflavus may be considered.

Nevertheless, cases with good visual outcomes have been described. In 3 case reports included in our systematic review, patients ended up with visual acuity 20/70, 20/40 and 20/60, respectively.^8,12,13 It is important to mention that in all 3 cases, after initial vitrectomy and vitreous sampling analysis, a second vitrectomy was performed, with addition of appropriate antibiotics based on the antibiogram. Intravitreal antibiotics of choice included amikacin (0.4 mg/0.1 mL) or combination of ampicillin (5 mg/0.1mL) and amikacin.

The intrinsic vancomycin resistance of E. casseliflavus has important clinical implications that impact treatment decisions, namely the duration of treatment and the need for close postoperative follow-up. Clinicians must ensure that the selected alternative antibiotics, either intraocular or systemic, are administered for an adequate duration to achieve complete resolution of the infection. Additionally, frequent monitoring and follow-up are crucial to assess the patient’s response to treatment and to detect any signs of relapse or complications. Clinicians must be vigilant in selecting alternative antibiotics based on susceptibility testing as well, and a multidisciplinary approach involving infectious disease specialists and microbiologists is often crucial in managing infections caused by this resistant pathogen.

One limitation of our systematic review is represented by the relatively small number of cases that were identified, a fact that could be attributed to potential publication bias. Furthermore, since our final selection was limited to case reports and case series, we were unable to perform a meta-analysis. As a result, our conclusions may be less robust. Nonetheless, we attempted to mitigate the risk of bias and enhance the quality of our analysis by employing the JBI critical appraisal checklist for each included case report.

Conclusions

In conclusion, the goal of this systematic review was to raise awareness among clinicians regarding E. casseliflavus as a potential cause of infectious endophthalmitis, which can be a vision-threatening infection if not treated promptly and adequately. The inherent resistance of E. casseliflavus to vancomycin renders management of such infections challenging, necessitating further clinical studies to define optimal antimicrobial treatment strategies.