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Successful salvage therapy of Fusarium

endophthalmitis secondary to keratitis:
an interventional case series
This article was published in the following Dove Press journal:
Clinical Ophthalmology
8 May 2012
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Grant M Comer Purpose: To describe a combination of treatment modalities used for the successful eradication
Maxwell S Stem of Fusarium endophthalmitis.
Stephen J Saxe Design: Interventional case series.
Participants: Three consecutive patients with keratitis-associated Fusarium endophthalmitis.
University of Michigan, Department
of Ophthalmology and Visual Sciences, Methods: After failure of traditional management options, a combination of intravitreal and
Ann Arbor, MI, USA long-term, high-dose systemic voriconazole, topical antifungal medications, and surgical
intervention, with penetrating keratoplasty, lensectomy, and endoscopic-guided pars plana
vitrectomy, was administered to each patient.
Results: All three cases achieved full resolution of the infection, with a final Snellen visual
acuity score of 20/50 to 20/70.
Conclusions: An aggressive combination of therapeutic modalities, including the
removal of subiris abscesses, might be needed for the successful resolution of Fusarium
endophthalmitis.
Keywords: endophthalmitis, fungal, fusarium, keratitis, keratoplasty, voriconazole

Introduction
Fusarium is a saprotrophic mold, with worldwide distribution, that is responsible for
destructive mycotic keratitis. In portions of the Southern United States, ­keratomycosis
accounts for 6% of all microbial keratitis cases, and Fusarium species comprise 62% of
fungal isolates.1 Although cases are often associated with trauma,1,2 a 2006 ­international
outbreak of Fusarium keratitis, secondary to ReNu with MoistureLoc contact
lens ­cleaning solution (Bausch and Lomb, Rochester, NY), produced at least 130
­confirmed cases in the United States alone.3 Two cases of contact lens-induced keratitis,
progressing to endophthalmitis, were reported due to this outbreak.4
Fusarium is visually destructive, due to its high rates of resistance against
many ­antifungal mediations,5 relentless infiltration into ocular tissues,6 mycotoxic-
ity,7,8 and intravascular invasion with occlusion.9 It can perforate the cornea and
produce an infiltrative endophthalmitis in over 6% of keratitis cases, which leaves at
least 60% of eyes with finger-counting or worse visual acuity, and 30% of eyes with
­phthisis, or requiring enucleation.6,10 This manuscript will describe the clinical course
and ­successful resolution of three consecutive cases of Fusarium endophthalmitis
Correspondence: Grant M Comer
W K Kellogg Eye Center, 1000 Wall secondary to keratitis. Two of the cases were the result of soft contact lens wearing;
Street, Ann Arbor, MI 48105, USA the final case resulted from traumatic injury to the cornea. All three cases illustrate
Tel +1 734 647 6344
Fax +1 734 2328181
a uniform combination of treatments, involving the removal of subiris abscesses, to
Email [email protected] sterilize the eye and achieve a Snellen visual acuity of 20/50 to 20/70.

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Dovepress © 2012 Comer et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
http://dx.doi.org/10.2147/OPTH.S31652 which permits unrestricted noncommercial use, provided the original work is properly cited.
Comer et al Dovepress

Methods conclusion of the surgery. Shortly afterwards, culture sensitivity

Review of patient records was approved by the Institutional results revealed resistance to amphotericin B deoxycholate
Review Board of the University of Michigan, and conforms to and ketoconazole. In addition, the minimum inhibitory
all privacy rules set forth by the Health Insurance Portability concentration (MIC) of voriconazole was .8 µg/mL, which
and Accountability Act. suggested poor sensitivity. Because of this high MIC and
the difficulty eradicating the infection previously, a fourth
Case 1 intravitreal voriconazole (100  µg) injection was given
A 32-year-old healthy female contact lens wearer was referred shortly after surgery, in addition to increasing the dose of
to the Cornea Service at our academic ophthalmology oral voriconazole to 400  mg twice-daily. The eye showed
institution with a 10-day history of increasing redness, pain, slow clinical improvement. The high-dose oral voriconazole
and blurring of vision in the right eye. She had previously and topical natamycin were discontinued after 3  months.
started treatment with topical ofloxacin (0.3%) and A repeat penetrating keratoplasty was later required due
prednisolone acetate (1%). At presentation, the examination to graft failure. The Snellen best-corrected visual acuity
revealed a Snellen visual acuity of 20/20 with a medium- measured 20/70 after 5 years of follow-up.
sized superficial corneal ulcer and indistinct infiltrate at the
margins. Corneal cultures were obtained, and prednisolone Case 2
acetate treatment was immediately discontinued. Three days A 48-year-old healthy female contact lens wearer was
after presentation, an emergent penetrating keratoplasty was referred to the Cornea Service at our institution with a
required for a corneal perforation. The cultures revealed 7-day history of increased redness, pain, and blurring
unspeciated Fusarium. The patient began treatment with of vision in the right eye. She had previously started
frequent topical natamycin (5%), amphotericin B deoxycholate treatment with a topical combination of tobramycin (0.3%)
(0.15%), as well as oral ketoconazole (200  mg per day). and dexamethasone (0.1%). At presentation, examination
Prednisolone acetate (1%) was also prescribed to prevent revealed a Snellen visual acuity of 20/400 with a central
graft rejection. Two weeks later, the patient was referred to the corneal ulcer and underlying infiltrate. A corneal smear
Retina Service because of increased corneal graft infiltration revealed f ilamentous elements. Dexamethasone and
and anterior segment inflammation with a new hypopyon. tobramycin were discontinued, and topical natamycin
Due to presumed intraocular invasion of Fusarium, 5 µg of (5%), amphotericin B deoxycholate (0.15%), and oral
amphotericin B deoxycholate was injected into the vitreous, voriconazole (200 mg per day) were initiated. The cultures
and oral voriconazole (VFEND®, Pfizer, New York, NY) revealed unspeciated Fusarium. Two weeks later, the patient
(200 mg two times per day) was substituted for ketoconazole. was referred to the Retina Service because of increased
The eye continued to worsen clinically over 4 days, with the corneal infiltration and anterior segment inflammation with
development of vitreous opacities on B-scan ultrasound. a new hypopyon (Figure 1A). Voriconazole (100 µg) was
An emergent 20-gauge pars plana vitrectomy, with cultures injected through the pars plana, and the oral voriconazole
and lensectomy, was performed with a repeat intraocular was increased to 400 mg twice-daily. However, new vitreous
injection of amphotericin B deoxycholate (5 µg) at the opacities on B-scan ultrasonography and worsening
conclusion of surgery. The cultures reconfirmed unspeciated anterior segment inflammation precipitated a penetrating
Fusarium, and were sent to another institution for sensitivity keratoplasty, 20-gauge pars plana vitrectomy with cultures,
analysis. Initial postoperative improvement was quickly lensectomy, and endoscopic exploration 2  days later.
supplanted by increasing intraocular inflammation, and the Subiris and ciliary body abscesses were visualized and
eye received a third pars plana injection of amphotericin excised during surgery. The surgical cultures failed to yield
B deoxycholate (5 µg), followed by two injections of organisms. However, histology of the extracted corneal
voriconazole (100 µg). However, intraocular inflammation button revealed persistent fungal elements. The intraocular
continued to worsen. A second vitrectomy was performed, inflammation slowly improved. However, an infiltrate
using endoscopic guidance because of significant corneal graft at the graft-host interface was suspicious for recurrent
edema. The camera revealed large subiris and ciliary body infection, and topical voriconazole (1%) was added to
abscesses, which were removed with the vitrectomy cutter the topical natamycin (5%), amphotericin B deoxycholate
(see Video http://youtu.be/SLvTMCQB8X0). A third (0.15%), and prednisolone acetate (1%) regimen. Despite
intravitreal voriconazole injection (100 µg) was given at the this, the corneal infiltrate continued to worsen and required

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Dovepress Successful salvage therapy of Fusarium endophthalmitis

Figure 1 Case 2. (A) The patient’s clinical condition, following 3 weeks of treatment with topical and oral antibiotics, with severe corneal infiltrate and hypopyon. (B) The
patient’s eye 4 months after initial presentation, with a clear corneal graft and a quiet eye.
Notes: The clinical result represents a combined approach of aggressive medical treatment with topical, oral, and intravitreal antibiotics, in conjunction with endoscopic pars
plana vitrectomy, involving lensectomy and removal of sub-iris abscesses, as well as two penetrating keratoplasties.

a second penetrating keratoplasty. The corneal button was continued to worsen, which prompted surgical intervention
negative for fungal elements. Four months postoperatively, with a penetrating keratoplasty, 20-gauge pars plana vitrectomy
the eye had no signs of recurrent infection (Figure  1B), with lensectomy, and endoscopic exploration. Multiple subiris
and the oral voriconazole was discontinued along with the and ciliary body abscesses were removed using endoscopic
topical antifungal medications. The Snellen best-corrected visualization. Postoperative management included: topical
visual acuity was 20/50 at 1.5 years of follow-up. amphotericin B deoxycholate (0.15%), natamycin (5%) and
cyclosporine (1%), oral voriconazole (400 mg twice-daily),
Case 3 and two additional voriconazole (100 µg) injections through
A 54-year-old healthy male was referred to the Cornea Service the pars plana. The corneal and intraocular inflammation
at our institution 4 days after he was struck in the left eye slowly resolved, and the medication regimen was maintained
by a tree branch. He had previously started treatment with a for 3 months. Culture sensitivities, reported nearly a month
combination of topical tobramycin (0.3%) and dexamethasone after the surgery, revealed minimum inhibitory concentrations
(0.1%) in addition to ciprofloxacin (0.3%). However the ocular of 4 µg/mL for amphotericin B and natamycin and .8 µg/
redness persisted, and visual acuity worsened. At presentation, mL for voriconazole. The best-corrected Snellen visual acuity
examination revealed a Snellen visual acuity of 20/30 with was 20/60 after 5 years of follow-up.
multifocal corneal infiltrates. Corneal cultures were obtained,
and the previously-prescribed drops were changed to topical Results
natamycin (5%), neomycin sulfate (0.5%), and moxifloxacin Each of the three consecutive cases was characterized by
(0.5%) empirically. Two days later, visual acuity had dropped culture-positive Fusarium keratitis with subsequent anterior
to hand motion with enlargement of the corneal ulcer and chamber invasion and vitreous involvement. The infection
development of anterior segment infiltration. However there failed to respond to several treatments, including a variety
was no evidence of vitritis on B-scan ultrasound. An aqueous of topical, intravitreal, and systemic antifungal medications.
culture was obtained. An aqueous culture was obtained, and The endophthalmitis eventually cleared with a multimodal
an empiric injection of voriconazole (100 ug) was given approach, including medical treatment with topical natamycin
for presumed fungal invasion. Topical amphotericin B and amphotericin B deoxycholate, multiple intraocular
deoxycholate (0.15%) and systemic voriconazole (200  mg voriconazole (VFEND®, Pfizer, New York, NY) injections,
twice-daily) were added to the regimen. The aqueous culture and high-dose, long-duration oral voriconazole (400  mg
revealed unspeciated Fusarium. Because the corneal and twice-daily). Surgical management included penetrating
anterior chamber inflammation failed to improve and a keratoplasty, ­endoscopic-guided pars plana vitrectomy
follow-up B-scan ultrasound demonstrated new vitreous with subiris abscess removal, and lensectomy. In each case,
opacities, voriconazole (100 µg) was again injected into clearance of the infection occurred after endoscopic removal
the vitreous cavity and the systemic voriconazole dose was of subiris and ciliary body abscesses. Both cases in which
increased to 400 mg twice-daily. However, the inflammation the sensitivity of Fusarium to voriconazole was measured

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demonstrated an MIC . 8  µg/mL. Despite this poor some successes with various combinations of these treat-
voriconazole sensitivity, the combined approach resulted in ments. However, larger case series6,10 describe a predomi-
sterilization of the eye, and a final Snellen visual acuity score nantly dismal outcome. A number of these traditional medical
of 20/50 to 20/70. and surgical modalities were incorporated without success
in Case 1. Therefore, we switched to oral and intraocular
Discussion voriconazole, in addition to novel surgical management. This
Fusarium endophthalmitis can result from penetrating new approach salvaged the eye, and was then applied to the
trauma,6 keratitis,10 and intraocular surgery11 in immuno- two subsequent cases with relatively successful outcomes.
competent individuals. It can also occur endogenously in Voriconazole, with broad-spectrum antifungal properties,
immunocompromised patients.9,12 The first two individuals high oral bioavailability, and rapid systemic absorption,
in this case series developed endophthalmitis from Fusarium was approved by the US Food and Drug Administration in
keratitis secondary to soft contact lens wear; the third patient 2002, for invasive Aspergillus, Fusarium, and Scedosporium
acquired endophthalmitis from trauma-induced Fusarium infections. Although it is off-label for ocular indications,
keratitis. several small descriptive reports have suggested that it is safe
Eradicating Fusarium endophthalmitis is notoriously dif- and effective when directed against Fusarium infections in
ficult. Persistence of the infection despite standard treatments10 human eyes.4,22–25 The MIC of voriconazole towards ocular
or delayed recurrence of infection can occur for multiple Fusarium isolates usually ranges between 2–8 µg/mL, with
reasons.13 First, Fusarium has high rates of resistance to some few cases of resistance.5 By contrast, Fusarium exhibits
antifungal medications – which was the situation in at least two relatively high resistance rates to fluconazole, itraconazole,
of these cases.5 Poor susceptibility to voriconazole is less com- miconazole, ketoconazole, posaconazole, flucytosine,
mon, but there are at least two other case reports that document and amphotericin B deoxycholate.5,11 Voriconazole also
resistance of Fusarium to voriconazole.14,15 Also, these cases demonstrates time-dependent activity, which suggests that
raise the possibility that refractory cases might be secondary maximizing the duration of exposure might optimize fungistatic
to undetected abscesses, which provide a nidus for persistent activity.26 We attempted to achieve an intraocular concentration
infection. Removal of the abscesses hidden beneath the iris of voriconazole consistently in excess of the typical MIC by
was the event that, ultimately, initiated clinical improvement utilizing both systemic and intravitreal routes.
in each of these cases. Finally, topical corticosteroids were Systemically administered voriconazole in a non-inflamed
being used at presentation in all the cases. In the first two human eye achieves an intravitreal concentration of 0.81–
cases, corticosteroids were used postoperatively to prevent 1.12 µg/mL.23,27 We felt that an elevated dose of 400 mg, two
graft rejection. Studies suggest that topical corticosteroids times per day, might better maximize long-term intraocular
might worsen Fusarium infection by inhibiting the antifungal concentrations. In conjunction with ­the Infectious Disease
phagocytic action of immune cells.16–18 Cyclosporine, which Service, we monitored liver function tests weekly and were
has both antifungal and antirejection properties, has dem- cognizant of potential adverse interactions with other sys-
onstrated effectiveness when used topically on therapeutic temic medications. Tu et al described two cases of Fusarium
keratoplasties related to mycotic keratitis and may be a viable endophthalmitis in which the patients were unable to tolerate
alternative to corticosteroids when a keratoplasty is required, oral voriconazole due to systemic t­oxicity. However, another
as was the approach in Case 3.16,19 review suggested that the majority of patients taking oral vori-
The older treatment modalities for ocular Fusarium conazole for this indication tolerated the therapy long enough
infections are convoluted. Medical options have included: to achieve clearance of the infection.15,28 All of our patients
topical natamycin6 amphotericin B deoxycholate,6 and clotri- were able to tolerate the higher dose for 3–4 months.
mazole;6 subconjunctival amphotericin B deoxycholate6 and Repeated intraocular injections of voriconazole were
miconazole;6 intracameral amphotericin B deoxycholate;6 added to maximize intraocular concentration. In keeping with
intravitreal amphotericin B deoxycholate; 6 systemic previous reports discussing the safe dosing of intravitreal vori-
miconazole6 thiobendazole,6 fluconazole,10 ketoconazole,10 conazole, we injected 100 µg through the pars plana to achieve
amphotericin B deoxycholate,20 amphotericin B lipid com- a presumed vitreous cavity concentration of approximately
plex,21 and flucytosine.20 Surgical approaches have included: 20–25 µg/mL.4,22,23,29–33 Injections were administered as fre-
penetrating keratoplasty,10 lensectomy,10 iridectomy,10 and quently as every 48 hours, since voriconazole has a relatively
pars plana vitrectomy.6,10 Case reports11,20 have described short half-life. In the rabbit vitreous, the half-life measured

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Dovepress Successful salvage therapy of Fusarium endophthalmitis

2.5 hours. However, clearance may be more rapid in rabbits in the treatment of Fusarium endophthalmitis, it is clear that
than in humans.34 The clearance rate most likely accelerated the removal of subiris and ciliary body abscesses seemed to
further following vitrectomy.35 be the unifying event that initiated clinical improvement in
In our patients, voriconazole was injected into the vitreous each case. Thus, this combination of treatments, including
cavity instead of into the anterior chamber to maximize the removal of abscesses, might decrease the morbidity of
the duration of action and minimize anterior segment Fusarium endophthalmitis and allow for improved visual
complications in these previously phakic eyes. However, outcomes.
a recent report described successful eradication of Fusarium
in the anterior chamber when doses of voriconazole (100 µg) Acknowledgments
were injected intracamerally on a daily basis for up to This work was supported by a Postdoctoral Clinical/Transla-
8 days.24 Alternatively, topical voriconazole (1%) has good tional Science Fellowship Award from the American Diabetes
corneal penetration and was shown to achieve a concentration Association-Merck.
of at least 6.5 µg/mL in the anterior chamber.4,22,36 If initiated Portions of this manuscript were presented as a poster at
when the infection is limited to the anterior segment, these the American Academy of Ophthalmology Annual Meeting,
approaches may avoid the morbidity of more invasive November, 2006, Las Vegas, NV.
procedures.
Once the infection reaches the vitreous, surgery is often
Disclosure
needed to augment therapy.6 Pflugfelder et al reported that
The authors have no financial interest in any of the products
four of six patients (67%) with Fusarium endophthalmitis discussed in this paper.
required penetrating keratoplasty, 83% required vitrectomy,
100% required lensectomy, 67% required iridectomy, and
67% were left with no light perception vision.6 Similarly,
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