Enterococcus gallinarum endophthalmitis and meningitis in an allogeneic hematopoietic stem cell transplant patient: A case report and literature review

Abstract

Endogenous endophthalmitis caused by Enterococcus gallinarum, an organism with intrinsic resistance to vancomycin, has rarely been reported. We present a case of persistent E. gallinarum bacteremia in a female recipient of hematopoietic stem cell transplant (HSCT) complicated by endophthalmitis and meningoventriculitis, resulting in a fatal outcome despite treatment with intravenous ampicillin and daptomycin. Treatment of endophthalmitis often presents a challenge due to the lack of options for antimicrobials with reliable ocular penetration. Therapeutic decisions can become particularly complex with the involvement of drug-resistant pathogens and host characteristics that limit the choice of antimicrobials due to drug toxicity. This case illustrates a rare manifestation of an opportunistic pathogen.

Case Presentation

Our patient was a 61-year-old woman who presented with 3 months of unexplained fevers and fatigue following a recent diagnosis of chronic myelomonocytic leukemia. A follow-up bone marrow biopsy demonstrated progression of her malignancy to acute myeloid leukemia. She received induction chemotherapy with cytarabine and daunorubicin; this course was complicated by deep vein thrombosis and neutropenic fever without an infectious diagnosis, for which she received 1 week of cefepime and piperacillin–tazobactam followed by several months of levofloxacin. She received a second course of induction chemotherapy due to minimal residual disease and ultimately achieved remission. One month later, on October 1, 2020, she underwent a haploidentical allogeneic HSCT; she received myeloablative conditioning with fludarabine, melphalan, and total body radiation. Following the transplant, she received tacrolimus, mycophenolate mofetil, and cyclophosphamide for graft-versus-host disease prophylaxis. Her antimicrobial prophylaxis included acyclovir, penicillin VK, levofloxacin, posaconazole, inhaled pentamidine, and letermovir (the patient was seropositive, and her donor was seronegative for cytomegalovirus [CMV]).

On the fourth post-transplant day (day +4), the patient developed new fevers, and following a negative infectious workup, she was diagnosed with cytokine release syndrome. She was treated empirically with cefepime. However, on day +14, she developed recrudescent fevers, which were now associated with rigours and large-volume, severe non-bloody watery diarrhea, and hematemesis. Because she remained profoundly neutropenic (total white blood cell count was 0.1 × 10⁹ cells/L), cefepime was switched to piperacillin–tazobactam and vancomycin. Blood cultures were drawn from her central venous catheter and two venipuncture sites; all grew Enterococcus gallinarum after 9 hours of incubation. These isolates tested susceptible to penicillin, ampicillin, daptomycin, and linezolid but were resistant to vancomycin. Vancomycin was switched to daptomycin after one dose, and her central venous catheter was removed on day +18. Daily blood cultures continued to grow E. gallinarum. Investigations to identify a potential source of infection, including computed tomography (CT) scan of head, chest, abdomen, and pelvis; transthoracic echocardiogram; bilateral upper-extremity venous Doppler ultrasounds; and whole-body positron emission tomography (PET)-CT scan were all negative. A transesophageal echocardiogram was not performed due to severe thrombocytopenia. A summary timeline of antimicrobial administration, investigations performed, and pertinent clinical status changes are included in Figure 1.

Figure 1:

Chronologic timeline of patient’s disease progression

CT = Computed tomography; PET = Positron emission tomography; EVD = External ventricular drain; CSF = Cerebrospinal fluid; LP  = Lumbar puncture

On day +21, she experienced speckled visual defects in her right eye, associated with pain, tearing, blurry vision, and photosensitivity. Her bedside eye exam was notable for hyphema, subconjunctival hemorrhage, afferent pupillary defect, and hand motion visual acuity (Figure 2A). Ophthalmoscopy revealed significant anterior chamber flare, fibrin, and diffuse retinal hemorrhage consistent with endophthalmitis. B-scan ultrasonography of the right eye showed dense vitreous opacity, probable posterior vitreous and choroidal detachment (Figure 2B). Magnetic resonance imaging (MRI) of the brain showed abnormal signal hyperintensity of the right globe without retro-bulbar involvement (Figure 2C). Vitreous fluid cultures grew E. gallinarum. We increased the daptomycin dose from 8 mg/kg to 12 mg/kg to optimize intraocular penetration. She also received intravitreous ceftazidime and vancomycin. A vitrectomy was not offered due to thrombocytopenia and her tenuous clinical status.

Figure 2:

(A) Right eye exam showing hyphema and subconjunctival hemorrhage; (B) B-scan of right eye showing posterior vitreous and choroidal detachment (red arrow heads); (C) Cross-sectional view of T2 MRI showing an abnormal signal intensity and enhancement of right globe (yellow arrow)

On day +25, the patient had neutrophil engraftment. Follow-up B-scan ultrasonography showed improvement in the choroidal detachment. Her blood cultures eventually cleared after 15 consecutive days of positive cultures on day +29.

On day +31, high-grade fevers returned with new encephalopathy. A repeat CT scan of the head showed new obstructive hydrocephalus, transependymal edema in the periventricular white matter, and layering material within the occipital horns of both lateral ventricles, likely representing purulent material within the cerebrospinal fluid (CSF). A lumbar puncture was performed with an opening pressure of 214 mm of water. CSF sample showed 947 total nucleated cells per µL (reference range (ref): 0–5 cells per µL) with 97% neutrophils, protein of 298 mg/dL (ref: 0–35 mg/dL), and glucose of 24 mg/dL (CSF-to-serum glucose ratio = 0.185 [ref: approximately 0.6]). CSF bacterial culture also grew E. gallinarum. The mean inhibitory concentrations of antimicrobials were identical for all test drugs between the isolates recovered from blood, vitreal fluid, and CSF. Piperacillin–tazobactam was switched to ampicillin, and daptomycin was continued. On day +32, she underwent urgent external ventricular drain (EVD) placement to manage her obstructive hydrocephalus and altered mental status. Although her mental status improved following the EVD placement, on day +40, she became obtunded with fixed pupils. CT of the head demonstrated migration of the drain and large intra-ventricular hemorrhage. She emergently had a second EVD placement. Her clinical status continued to deteriorate with ongoing bleeding and EVD malfunction. Following a family conference, the patient was transitioned to comfort care, and she peacefully died on day +47.

Discussion

Enterococcus gallinarum, as with other Enterococcus species, is a typical colonizer of the human gastrointestinal tract (1). Although its pathogenicity is not completely understood, E. gallinarum is much less commonly implicated in infections than E. faecalis and E. faecium. Diagnoses of hematological malignancy, cholangitis, and neutropenia favour the development of bacteremia with non-E. faecalis, non-E. faecium enterococci (2). In one study, over 70% of patients with E. gallinarum had previous biliary disease, highlighting an important predisposing factor (3). Rare cases of deep-seated infections with E. gallinarum have been reported, including endocarditis, meningitis, and osteoarticular infections (4–6).

To identify other cases of E. gallinarum endophthalmitis, we searched MEDLINE, PubMed, and Google Scholar for English language articles using the medical subject heading (MeSH) database headings “Enterococc*” OR “Enterococcus gallinarum” OR “VRE” OR “vancomycin resistant enterococc*” AND “endophthalmitis” OR “endogenous endophthalmitis” OR “ocular infection” OR “eye infection”. After appropriate reports were identified, we reviewed their references and other articles that cited these. We identified two case reports of E. gallinarum endophthalmitis (Table 1) and one case series of enterococcal endophthalmitis, which included four cases with E. gallinarum (no specific details to these cases are provided) (7–9). The first of the two described cases was of a young man who developed a polymicrobial infection with E. gallinarum and Acinetobacter sp after sustaining a penetrating eye injury and subsequent intraocular foreign body (7). He was treated with 2 weeks of systemic ampicillin, clindamycin and moxifloxacin, intravitreal vancomycin, topical gentamicin, and several surgical interventions. Despite initially having a retinal detachment, he improved with therapy and ultimately achieved 20/80 visual acuity after 7 months of follow-up (7). The second described case was a woman with acute myeloid leukemia and prolonged pancytopenia who became bacteremic with E. gallinarum and subsequently seeded her eye; she was successfully treated with oral linezolid, intravitreal vancomycin, ceftazidime, amikacin and voriconazole, and vitrectomy (8). She received a haploidentical HSCT 4 months following this infection without any recurrent ophthalmic disease. The latter case and that of our patient are similar in the significant degree of myelosuppression present and preceding diarrhea and mucositis, which are likely required to facilitate endophthalmitis with this organism in the absence of penetrating eye injury. Several reported cases of E. casseliflavus endophthalmitis have occurred following ocular injury, which supports this hypothesis.

Table 1:

Reported cases of Enterococcus gallinarum endophthalmitis^*

Reference	Country	Gender	Age (years)	Presentation	Predisposing factors	Treatments	Outcome
Current report	United States	Female	61	Bacteremia, visual field defects, ocular pain	Leukemia, pancytopenia, mucositis	Systemic = 39 days of daptomycin, piperacillin–tazobactam, and ampicillin	Died
						Intravitreal = vancomycin, ceftazidime
Hillier et al, 2013 (7)†	Canada	Male	38	Decreased visual acuity (only to light and motion)	Penetrating ocular injury with retained foreign metal body	Systemic = 2 weeks of ampicillin, clindamycin, moxifloxacin	Rapid improvement in visual acuity to 20/80 with aphakic correction
						Intravitreal = vancomycin
						Topical = gentamicin
						Surgical = Primary repair, pars plana lensectomy, vitrectomy, removal of foreign body, and partial air-fluid exchange (at presentation)
Shahin et al, 2020 (8)	United States	Male	70	Bacteremia, ocular pain, photophobia	Leukemia, pancytopenia, mucositis	Systemic = 3 weeks of linezolid, prednisone	80% recovery of visual acuity
						Intravitreal = vancomycin, ceftazidime, voriconazole, amikacin
						Surgical = pars plana vitrectomy (1 week after presentation)

* Four cases from India published by Dave et al, 2020 (9) are not included due to no description of presentations or outcomes

† Polymicrobial infection with Enterococcus gallinarum and Acinetobacter sp

E. gallinarum and its phylogenetic neighbour, E. casseliflavus, often harbour a constitutively expressed chromosomal vanC gene, which confers intrinsic low-to-intermediate level vancomycin resistance by encoding D-ala-D-ser instead of D-ala-D-ala in the peptidoglycan protein precursors (1). The preferred therapies for these organisms include ampicillin, daptomycin, linezolid, and nitrofurantoin, depending on the minimum inhibitory concentrations and site of infection (10). Our case highlights an essential aspect of treating enterococcal infections involving the anterior and intermediate ocular compartments and the central nervous system.

Penetration of antimicrobials into the CSF and vitreous humor across non-inflamed barriers is determined by a combination of molecular qualities, including size, lipophilicity, ionization, and plasma protein-binding (11,12). To maintain effective levels in the CSF, antimicrobials must further evade active transport mechanisms (11). The blood-retinal barrier, consisting of the retinal capillaries’ endothelia and the retinal pigmented epithelium, is an efficient filter of large molecules and proteins; however, in the absence of active transport, drug elimination is relatively slower (12). Penicillin and ampicillin have adequate penetration across the inflamed blood-brain barrier; they are essential in the therapy of bacterial meningitis caused by susceptible organisms, such as Neisseria meningitidis and Listeria monocytogenes, respectively (11). However, data on their penetration into the eye are unclear, and there are no human studies to address this. Studies in rabbits have shown unsatisfactory concentrations of ampicillin and penicillin in the anterior chamber of the eye following intravenous administration with and without probenecid (13,14). Standard management for bacterial endophthalmitis includes intravitreal injections of ceftazidime and vancomycin; neither of these drugs is active against vancomycin-resistant enterococci (VRE). Cases of VRE endophthalmitis have been successfully treated with oral or intravenous linezolid, but linezolid’s significant risk of myelosuppression limits its use in the setting of pancytopenia; others have used systemic moxifloxacin, linezolid with aminoglycosides or high-dose ampicillin with aminoglycosides (10,15). In all reports, systemic antimicrobials were adjunctive to intravitreal injections or vitrectomy. Therefore, a multidisciplinary approach to managing ophthalmic infections with expedited assessment and management by ophthalmology is critical.

The management of endophthalmitis in our patient was particularly challenging given her poor clinical status with multisystem organ dysfunction, concomitant central nervous system infection, profound myelosuppression, and infection with an antimicrobial-resistant organism. This case highlights the catastrophic potential of an opportunistic pathogen in an immunosuppressed host; similar cases involving unusual manifestations of atypical organisms may increase with the widespread use of broad-spectrum antimicrobials in immunocompromised patients. An understanding of antimicrobial pharmacokinetics is essential for the successful treatment of compartmentalized infections. Accordingly, for intraocular infections, both system and intravitreal therapies should be used to optimize drugs’ ocular penetration, and vitrectomy should be considered when feasible.

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