Endophthalmitis caused by Burkholderia cepacia complex (BCC): Clinical characteristics, antibiotic susceptibilities, and treatment outcomes

Purpose To report the clinical characteristics, antibiotic susceptibilities, and review the literature of Burkholderia cepacia complex (BCC) associated endophthalmitis. Study design: Retrospective, observational case series Methods Clinical and microbiology records were reviewed for patients evaluated at the Bascom Palmer Eye Institute and diagnosed with culture-confirmed endophthalmitis due to BCC. Antibiotic susceptibility profiles were generated using standard microbiologic protocols via an automated VITEK system. Results Endophthalmitis associated with BCC was diagnosed in three patients. Infection occurred in the setting of post-penetrating keratoplasty (PKP), glaucoma filtering surgery, and suspected trauma. All isolates demonstrated in vitro susceptibility to ceftazidime and meropenem. Presenting visual acuity (VA) ranged from hand motion to light perception. Initial treatment strategies included intravitreal ceftazidime (2.25 mg/0.1 mL) and vancomycin (1.0 mg/0.1mL) injections with fortified topical antibiotics in 2 patients, and surgical debridement of a corneoscleral melt with patch graft along with both topical fortified antibiotics oral antibiotics in the third patient. In all 3 patients, there was no VA improvement at last follow-up, as 2 eyes ultimately underwent enucleation and 1 eye exhibited phthisis bulbi at last follow-up. BCC related endophthalmitis was reviewed among 13 reports. Treatment outcomes were generally poor and antibiotic resistance was common. These BCC isolates cases demonstrated broad resistance patterns, with susceptibilities to ceftazidime (58%), ciprofloxacin (53%), and gentamicin (33%). Conclusions Endophthalmitis caused by B. cepacia is a rare clinical entity with generally poor visual outcomes despite prompt treatment with appropriate antibiotics.


Introduction/Background
Bacterial endophthalmitis is most often caused by gram-positive organisms, but gram-negative organisms account for up to 30 percent of cases.(Relhan & Flynn 2017, Irvine, et al. 1992) Gram-negative endophthalmitis are often associated with unfavorable VA outcomes.(EVS 1995, Sengillo, et al. 2020) The Burkholderia cepacia complex (BCC), previously classi ed as part of the Pseudomonas genus, is a group of at least 20 closely related species of rare gram-negative, oxidase-positive, non-fermenting bacillary organisms.(Ragupathi & Veeraraghavan 2019, Lipuma 2005) Found in soil, water, plants, industrial settings, and hospitals, BCC is ubiquitous in the environment and harbors a large genome encoding for many virulence factors which provide natural antibiotic resistance.(Uehlinger, et al. 2009, Zhang, et al. 2001) BCC has been implicated in outbreaks from contaminated surgical compounds, (Lalitha, et al. 2014, Sunenshine, et al. 2009) as well as pharmaceutical products such as nebulization solutions, hand sanitizers and mouthwash.(Balkhy, et al. 2005, Lind, et al. 2021, Tavares, et al. 2020) Tavares and colleagues reported viable BCC isolates from pharmaceutical-grade, nutrient-de cient, saline solutions containing biocidal preservatives as much as 16 months later in two BCC species.(Tavares, et al. 2020) Clinical and ecological distinction among the various BCC species remain to be described, and indeed, many clinical laboratories struggle with species speci c identi cation using standard automated commercial systems.(Ragupathi & Veeraraghavan 2019, Lama, et al. 2021) Cystic brosis, chronic granulomatous disease, and other causes of immune compromise have been cited as predisposing risk factors for BCC infections (Peeters, et al. 2009), although no such association has been reported yet for ocular infections.
Ocular BCC infections are rare and present with a signi cant degree of clinical variation.In a recent report of 6 cases of B. contaminans endophthalmitis following cataract surgery, time to onset of symptoms was 12-112 days, with 5 of 6 cases having at least one recurrence of symptoms following treatment.(Lind, et al. 2021) Most case series of BCC endophthalmitis reported poor visual outcomes that often result in phthisis, enucleation or visual acuity of light perception (Deka, et al. 2018, Eser, et  respectively).In a large review, BCC accounted for 1.8% (14/744) (Sachdeva, et al. 2011) of culture positive cases of endophthalmitis, which occurred after cataract surgery in 85% of cases (29/34), (Okonkwo, et al. 2019) and post-penetrating keratoplasty (PKP), LASIK, (Reddy, et al. 2013) intravitreal anti-VEGF injection, and ltering surgery in the remainder of cases.
Herein we report 3 cases of B. cepacia endophthalmitis evaluated and treated at our institution.We also review the literature of the other BCC endophthalmitis with particular attention to the reported antibiotic susceptibilities and clinical outcomes.

Patients and Methods
This retrospective consecutive case series conducted at Bascom Palmer Eye Institute examined the bacterial isolates of patients with culture-positive B. cepacia endophthalmitis (Table 1).Data collected from charts included patient demographics, preexisting ocular and systemic conditions, exam ndings, treatment administered, operative reports, and microbiology laboratory results (Table 2).Phenotypic antibiotic resistance patterns reported here were obtained from minimum inhibitory concentration values using the automatic system Vitek 2 (bioMérieux, Durham, NC).

Case 1
An 80-year-old male presented with complaints of redness and discharge two weeks following repeat penetrating keratoplasty with amniotic membrane graft and subconjunctival bevacizumab injection for corneal decompensation in the setting of multiple prior surgeries.Ocular comorbidities included a remote history of cataract surgery and ExPRESS shunt implantation, BGI for neovascular glaucoma, and a central retinal vascular occlusion.Prior to the penetrating keratoplasty surgery, baseline VA was noted to be poor (hand motion).Exam revealed purulent discharge, hypopyon, shallow anterior chamber (AC), and dense vitritis on B-scan echography.An AC paracentesis was performed for culture after a failed vitreous tap.Intravitreal vancomycin (1.0 mg/0.1mL) and ceftazidime (2.25 mg/0.1 mL) were injected.Topical forti ed tobramycin and vancomycin were initiated.VA improved to count ngers the following day, however, exam revealed possible periorbital extension with restricted ocular movement for which oral amoxicillin-clavulanate was started.The following day, further clinical decline was noted with decrease in VA to hand motion, increasing hypopyon size, and pain.Given poor visual potential and patient preference, the eye was enucleated 2 days following initial presentation.

Case 2
A 66-year-old female presented with a painful red eye for 2 weeks.Ocular history included a prior glaucoma drainage implant (GDI) at an outside facility 6 months ago.Of note, VA prior to GDI was LP.
Exam at presentation included hypopyon and brin surrounding the tube in the AC.B-scan ultrasound showed dense vitreous membranes.A vitreous culture was performed, and vancomycin (1.0 mg/0.1mL),ceftazidime (2.25 mg/0.1 mL), and dexamethasone were injected.Topical forti ed vancomycin 25mg/ml, tobramycin 14mg/ml, atropine 1% solution, and 1% prednisolone acetate were also initiated and eventually deescalated to moxi oxacin following identi cation of B. cepacia.At 8 days following initial presentation, her pain improved but visual acuity decreased to no light perception (NLP); there was a persistent hypopyon and B-scan echography demonstrated a retinal detachment.At six weeks follow-up, infection was resolved but the eye remained NLP with 360-degree choroidal and retinal detachments with phthisical changes.The eye was enucleated 3 years following initial presentation due poor prognosis and new exposure of the GDI and IOL.

Case 3
A 62-year-old male presented with a 2-week history of progressive eye pain.The patient had prior cataract surgery 3 years earlier and reported an episode of blunt trauma (an elbow to the eye) approximately 2 weeks prior to symptom onset with stable subjective vision until the day of presentation.Presenting VA was LP and initial examination revealed complete corneal opaci cation with central corneal ulceration and 360 choroidal detachment on B-scan echography.The patient was taken to surgery for corneoscleral debridement of necrotic tissue and implantation of a corneal patch graft.Intraoperative biopsy was performed.The patient was treated with forti ed topical vancomycin, tobramycin, with the addition of moxi oxacin upon identi cation of B. cepacia, as well as oral levo oxacin followed by oral cipro oxacin.Once fungal infection was ruled out, topical prednisolone was initiated with subsequent addition of oral prednisolone and subtenon's triamcinolone.Despite aggressive topical and periorbital treatment, at twoweek follow-up, B-scan ultrasound showed retinal detachment, dense vitritis, and subretinal opacities suggestive of endophthalmitis.Due to poor prognosis, early phthisis bulbi, and an unsalvageable eye, a vitreous tap was deferred.Comfort measures and enucleation were recommended.The patient was subsequently lost-to-follow-up.

Discussion
In the review of the literature, 13 additional reports of BCC related endophthalmitis were identi ed accounting for 56 cases (Table 3).BCC related corneal ulcers or systemic infections were not included in this review.The reports range from 1992 with Irvine and colleagues to Lind and colleagues reporting 6 cases in 2021.78% (44/56) of cases were preceded by cataract surgery, 9% (5/56) occurred after trauma, and remainder occurring after intravitreal injections, vitrectomy, and corneal transplantation.Time to onset ranged from 2 days to 6 months from the identi ed inciting event, with an average of 36 days and median of 20 days.Recurrent infection was described in 13 cases, of which 6 cases had more than one recurrence.Final visual outcomes also varied signi cantly.One quarter of cases (14/56) had visions of 20/40 or better, with 6 of the 13 cases reported by Lind et al.An additional 32% (18/56) achieved a nal VA between 20/40 and 20/200.The remainder had poor visual outcomes of which at least 7 ended in phthisis or enucleation and 3 had retinal detachments by the end of respective follow up periods.Recurrence was also common with reports of at least 13/56 cases.
Among the 10 reports that described antibiotic susceptibilities, each tested and reported different antibiotic sensitivity panels (Table 4).Treatment strategies generally followed EVS guidelines with intravitreal vancomycin (1 mg/0.1 mL), ceftazidime (2.25 mg/0.1 mL).Vitrectomy with silicone oil was also a common therapy when presenting VA was LP or worse.Of the antibiotics tested in at least 3 reports, there was evidence of at least one BCC strain with resistance reported by one of the remaining 8 studies analyzed.Both Lind et al. and Lalitha et al. reported strains sensitive to piperacillin/tazobactam. Case 3 reported in our cohort, however, displayed resistance to piperacillin/tazobactam. Ceftazidime was the most tested, utilized, and most commonly sensitive antibiotic at 68% (30 cases were sensitive, 16 were resistant, 2 were reported as "moderate" sensitivity, 1 was not reported).Of note, Deb et  cases occurred after cataract surgery, 1 following PKP, and 4 in the setting of trauma.(Sachdeva, et al. 2011) In a recent literature review, Okonkwo et al (2019) found 34 cases of post-surgical, culturecon rmed endophthalmitis between 1992-2018 among 8 reports, of which 85% occurred following cataract surgery and the remainder occurring after PKP, intravitreal injections (Okonkwo, et al. 2020, Saffra & Moriarty 2014), and vitrectomies.(Okonkwo, et al. 2019) BCC isolates often display signi cant antibiotic resistance pro les in vitro.(Irvine, et al. 1992) A recent report of the molecular analysis of B. contaminans isolate from a polymicrobial corneal ulcer showed inherent resistance to uoroquinolones, cephalosporins, carbapenems, monobactam, aminoglycosides, and sulfonamides while susceptible to tetracylclines, meropenem, and ceftazidime.(Lama, et al. 2021) Outcomes for BCC endophthalmitis varied signi cantly across the 13 reports reviewed.Clear trends remain di cult to extrapolate as context and treatment strategies varied widely.Additionally, the wide degree of antibiotic resistance variation among the BCC strains, discussed further below, requires an individualized approach to care.Indeed, recurrence was noted in 13 cases, 6 of which had multiple episodes, while 5 cases reported by Deb et al. treated with an antibiotic subsequently noted as sensitive had an inadequate response.
Review of the susceptibilities of BCC related endophthalmitis cases published in the literature demonstrates a diversity of antibiotic sensitivities among the virulent strains described as well as diverse panels of antibiotic susceptibilities tested.Ceftazidime was the most commonly tested and most commonly sensitive antibiotic, followed by cipro oxacin and gentamicin.Pipercillin/tazobactam stands out as sensitive in 19/19 cases.However, this represents only two reports (Lind et al and Lalitha et al) which described two single outbreak clusters respectively, and case #3 described in the present report displayed piperacillin/tazobactam resistance.These results align well with the various resistance mechanisms employed by this bacterial genus.Given the broad resistance patterns seen, identi cation of BCC as well Pseudomonas, which is often initially misidenti ed for BCC, may bene t from a broader susceptibility panel examination and lower threshold to broaden therapeutic choice of agents.
In the current study, all three isolates were susceptible to ceftazidime (Table 1) which were given as intravitreal injections to patient 1 and patient 2. All patients received topical forti ed vancomycin and tobramycin.In addition, all three patients received topical moxi oxacin upon identi cation of the causative organism.Despite in vitro susceptibility testing, multiple clinical and laboratory studies have substantiated the observed treatment failure seen in many patients.Although some have attributed this to inadequate antibiotic concentrations, factors like broad intrinsic antibiotic resistance, (Zhang, et al. 2001) bio lm formation (Desai, et al. 1998), and phase of growth (Peeters, et al. 2009) affect the resistance pro le.Various studies have shown potential BCC resistance to all the major antibiotic classes, including polymyxins, aminoglycosides, (Cox & Wilkinson 1991) ß-lactams, (Poirel, et al. 2009) uoroquinolones (Zhang, et al. 2001) and tetracyclines.(Burns, et al. 1996) These factors might support an earlier surgical intervention with vitrectomy.(EVS1995) All 3 patients had previous intraocular surgery.Cataract surgery is the most common cited preceding factor to BCC endophthalmitis.(Ornek, et al. 2009, Sachdeva, et al. 2011) Time to presentation is also quite variable, as seen among our 3 cases.(Lalitha, et al. 2014, Sachdeva, et al. 2011) Although cases of BCC endophthalmitis generally meet the European Society of Cataract & Refractive Surgeons (ESCRS) criteria for acute post-operative endophthalmitis of within 6 weeks of surgery, it is notable that only 14-22% of acute endophthalmitis is seen beyond 2 weeks of surgery while BCC on average presents 2-6 weeks after initial insult.(Barry, et al. 2013) And while prior studies comparing outcomes of acute vs delayed onset endophthalmitis found better outcomes with the more insidious forms, (Shirodkar, et al. 2012) delayed onset cases of BCC do not follow this general trend.(Lalitha, et al. 2014, Lind, et al. 2021, Sachdeva, et al. 2011, Sunenshine, et al. 2009) A recent outbreak of endophthalmitis at a surgical center in Norway included 6 patients in the period from 1/4/2019 to 1/28/2019 with B. cepacia complex linked to a contaminated fresh air ventilation system.(Lind et al. 2021, Spilker et al. 2022) All 6 eyes had severe vision loss and required prolonged treatment course.In sharp contrast with other prior reports, Lind and colleagues reported good visual outcomes ( nal vision of 20/25 or better) among 6 cases of BCC endophthalmitis following cataract surgery treated with vitrectomy, lensectomy with complete removal of the capsular bag, and repeated intravitreal antibiotic injections.(Lind, et al. 2021) These cases along with a report by Okonkwo (Okonkwo, et al. 2020) suggest an important role in capsular bag removal during initial vitrectomy as means of preventing recurrence which has been documented in other prior reports.
In the non-ophthalmic literature, B. cepacia infection has also been associated with immunocompromise, particularly in patients with cystic brosis and chronic granulomatous disease (CGD).(Peeters, et al. 2009) None of our patients had a history of cystic brosis, CGD or known immunocompromise.Several case series have also found contaminated surgical or pharmacologic agents as sources of cluster infections which was not suspected as the likely cause in our case series.(Lalitha, et al. 2014, Sunenshine, et al. 2009) The current study adds 3 cases B. cepacia endophthalmitis, a rare clinical entity, to the body of literature.Our review of antibiotic sensitivity pro les among BCC endophthalmitis reports is the largest review to date and builds on prior reports of broad antibiotic resistances seen in BCC.
al. 2006, Lalitha, et al. 2014, Okonkwo ON, et al. 2019, Okonkwo, et al. 2018, Pathengay, et al. 2005, Sachdeva, et al. 2011, Sunenshine, et al. 2009).Deb et al. reported an outbreak of 5 cases of post-operative BCC endophthalmitis all of which failed to respond following vitreous tap and injection of vancomycin and ceftazidime, despite subsequent demonstration of ceftazidime susceptibility.4 cases underwent vitrectomies with additional injection of meropenem, all achieving vision of 20/200 or better, of which 2 cases attained nal vision of 20/60.(Deb,et al. 2022) In signi cant contrast, Lind et al. reported all 6 cases having good visual outcomes of ≥ 0.8.(Lind, et al. 2021) Two other case reports of BCC endophthalmitis by Okonkwo (Okonkwo, et al. 2020) and Saffra (Saffra & Moriarty 2014) following anti-VEGF injections with relatively quick onset (4 days (Okonkwo, et al. 2020) and 11 days (Saffra & Moriarty 2014) following injection), treated with pars plana vitrectomy and intravitreal antibiotic injections also reported favorable visual outcomes (20/60 (Okonkwo, et al. 2020) and 20/30 (Saffra & Moriarty 2014) AbbreviationsAC: anterior chamber al. reported 5 cases initially treated with vitreous tap and injection of vancomycin plus ceftazidime ultimately requiring additional pars plana vitrectomy and injection of meropenem due to inadequate initial response yet reported sensitivity to ceftazidime in all isolates.(Debet al. 2022) Fluoroquinolone sensitivities were reported by 9/10 studies, with cipro oxacin being the most commonly tested showing 53% sensitivity among cases tested (21/40).Aminoglycosides were also commonly tested, gentamicin showing 33% sensitivity (13/40) and amikacin showing 20% sensitivity (8/41).Reported cases of BCC endophthalmitis are rare.The rst case of B. cepacia endophthalmitis was reported by Del Piero et al. in 1985 following trabeculectomy and extracapsular cataract extraction.(DelPiero, et al. 1985) In the largest case series to date, Sachdeva et al. reported 14 cases of BCC endophthalmitis out of 744 cases in the LV Prasad Endophthalmitis registry between 2003-2008: 9