CASE REPORT
`
`Clinical Response of Contact Lens—Associated Fungal
`Keratitis to Topical Fluoroquinolone Therapy
`
`Wuqaas M. Munir, MD,* Steven I. Rosenfeld, MD, * Ira Udell, MD,7‘ Darlene Miller, DHSC, MPH, *
`Carol L. Karp, MD, * and Eduardo C. Alfonso, MD*
`
`Purpose: To report 5 cases of fungal keratitis associated with con-
`tact lens wear that resolved or significantly improved without anti-
`fungal therapy.
`
`Methods: Observational case report of 5 patients with a history of
`contact
`lens wear who presented with infectious keratitis. Two
`patients had growth of fungal species on corneal microbiologic
`cultures, and of the remaining 3 patients, 2 showed fungal elements
`on confocal microscopy. All 5 patients exhibited growth of fungal
`species on contact lens microbiologic cultures. All patients received
`topical fluoroquinolone therapy as initial treatment.
`
`Results: In 3 cases, of whom 2 were treated with moxifloxacin
`0.5%, the keratomycosis resolved completely on topical fluoroquin—
`olone therapy. One case was
`switched to topical
`tobramycin
`14 mg/mL and cefazolin 50 mg/mL with complete resolution of
`the infection. The final case showed marked initial
`improvement
`on fluoroquinolone therapy but was
`subsequently treated with
`natamycin 5%.
`
`Conclusions: Fungal keratitis associated with soft contact lens wear
`may occasionally present in a less aggressive form. Topical fluoro-
`quinolone therapy may be an adjunct to the innate immune response
`in eradicating less fulminant keratomycosis.
`
`Key Words: contact
`keratomycosis
`
`lens,
`
`fluoroquinolone,
`
`fungus, keratitis,
`
`(Cornea 2007;26:6217624)
`
`Keratomycosis can be associated with devastating loss
`of vision. Not only can fungal keratitis cause severe
`corneal damage, but intraocular structures may be irreversibly
`damaged through invasion of the anterior chamber.1’2 Occa-
`sionally, severe fungal keratitis may lead to endophthalrnitis.3
`
`Historically, soft contact lens wear has had a low prev-
`alence of associated fungal keratitis.}10 However, we recently
`reported an alarming escalation of soft contact lensiassociated
`Fusarium keratitis in south Florida.11 Many of these cases
`resulted in a protracted course of treatment with loss of
`visual acuity. Conversely, we report 5 cases of keratomycosis
`associated with contact lens wear in which complete resolution
`or significant improvement was obtained without institution
`of specific antifungal therapy (Table 1).
`
`CASE REPORTS
`
`Case 1
`A 41-year-old, soft contact lensiwearing woman was evalu-
`ated for infectious keratitis ofthe left eye. Her history was remarkable
`for use of an unspecified brand of Renu contact
`lens solution
`(Bausch & Lomb, Rochester, NY). On presentation, she was admin-
`istering moxifloxacin 0.5% topically to the left eye every hour.
`Best-corrected visual acuity was 20/20 in the right eye and 20/40
`in the left eye. Examination revealed a 3-mm central, midstromal,
`hazy infiltrate in the left cornea, without overlying epithelial defect.
`Aggressive corneal microbiologic cultures and smears were per-
`formed. Contact lens paraphernalia including the solution, contact
`lens, and contact lens case were also sent for microbiologic exam-
`ination. Microscopic examination of smears with Gram stain was
`negative for organisms. Confocal microscopy was positive for fungal
`elements (Fig. l). The patient was continued on topical moxifloxacin
`0.5% every hour. Corneal cultures were negative for growth; how-
`ever, both the contact lens and contact lens case showed growth
`of Bipolaris species. Six days after initiation of therapy, the patient
`continued to improve, and therefore specific antifungal
`therapy
`was not initiated. By 14 days after symptom onset, the infiltrate was
`quiet, and topical moxifloxacin 0.5% was discontinued (Fig. 2). The
`patient remained free of recurrence at her 1-month follow-up, with
`best-corrected visual acuity of 20/40 in the left eye and a central
`corneal scar.
`
`Case 2
`
`
`
`Received for publication July ll, 2006; revision received January 10, 2007;
`accepted January 10, 2007.
`From the *Bascom Palmer Eye Institute, University of Miami, Miller School
`of Medicine, Miami, FL; and the TDepartment of Ophthalmology, North
`Shore LIJ Health System, Albert Einstein College of Medicine, Long
`Island, NY.
`the Ocular Microbiology and Immunology Group
`Presented in part at
`Meeting, November 10, 2006, Las Vegas, NV.
`Reprints: Eduardo C. Alfonso, Bascom Palmer Eye Institute, 900 NW 17th
`Street, Miami, FL 33136 (e—mail: ealfonso@med.miami.edu).
`Copyright © 2007 by Lippincott Williams & Wilkins
`
`A 16-year-old girl who wore contact lenses presented with
`pain and redness to the left eye for 1 day, with similar symptom onset
`in the right eye since the morning of examination. She reported use
`of Renu MoistureLoc contact lens solution (Bausch & Lomb). Her
`best-corrected visual acuity was 20/40 in the right eye and 20/30 in
`the left eye with significant photophobia. Slit-lamp biomicroscopy
`showed a pinpoint, paracentral stromal infiltrate with focal overlying
`epithelial defect in the right eye. Examination of the left eye showed
`a 2-mm temporal area of multifocal, anterior stromal infiltration
`and punctate epithelial erosions without frank epithelial defect.
`Diagnostic corneal scraping was performed for microbiologic cul-
`tures and smears. The contact lens, solution, and case were also sent
`
`Cornea 0 Volume 26, Number 5, June 2007
`
`621
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`ALCON 2138
`Apotex Inc. v. Alcon Pharmaceuticals, Ltd.
`Case |PR2013—00012
`
`

`

`Munir er al
`
`Cornea 0 Volume 26, Number 5, June 2007
`
`TABLE 1. Demographics, Clinical Characteristics, and Treatments by Patient
`Age in
`Corneal Culture
`Contact Lens
`Confocal
`Clinical
`Initial
`Final
`
`Years (Sex)
`(Organism)
`Cultured Organism
`Microscopy
`Appearance
`Treatment
`Treatment
`
`41 (F)
`16 (F)
`14 (F)
`
`Negative
`Negative
`Fusarium species
`
`Bipolaris species
`Fusarium species
`Fusarium species
`
`Moxifloxacin 05%
`Moxifloxacin 05%
`Tobramycin 14 mg/mL,
`cefazolin 50 mg/mL
`Natamycin 5%
`Moxifloxacin 05%
`Multifocal
`Positive
`Fusarium species
`Fusarium species
`40 (F)
`
`40 (M) Gatifloxacin 0.3% Negative Fusarium species Positive Multifocal Gatifloxacin 0,3%
`
`
`
`
`
`*Not performed
`
`Positive
`*
`*
`
`Midstromal
`Multifocal
`Multifocal
`
`Moxifloxacin 05%
`Moxifloxacin 05%
`Ofloxacin 0.3%
`
`for cultivation. Microscopic examination of smears with Gram stain
`was negative for organisms. Initial therapy was begun with topical
`moxifloxacin 0.5% hourly in both eyes. Two days after presentation,
`mold growth was apparent on microbiologic culture of the con-
`tact
`lens. However,
`the patient continued to experience marked
`improvement both symptomatically and clinically. Therefore, topical
`moxifloxacin 0.5% was continued. The mold was later identified as
`Fusarium species. Moxifloxacin was discontinued on the 13th day,
`with resolution of the infiltrate in both eyes with residual scar
`formation.
`
`Case 3
`
`A 14-year-old girl who wore soft contact lenses and used
`Renu MoistureLoc contact lens solution was referred for further
`
`treatment of infectious keratitis of the left eye (data from case
`reported in part previously”). Prior therapy included topical ofloxacin
`0.3%. Best-corrected visual acuity was 20/20 in the right eye and
`20/25 in the left eye. Slit-lamp examination showed 2 adjacent, l-mm
`anterior stromal infiltrates in the nasal cornea, with punctate overlying
`the epithelial defect. Ofloxacin 0.3% was continued topically. Despite
`initial improvement with apparent resolution of the epithelial defect,
`the patient returned 7 days after initial presentation with a new l-mm
`anterior stromal infiltrate superior to the previous site of involvement
`in the left eye (Fig. 3). Corneal microbiologic cultures and smears
`were performed, and contact lens paraphernalia were sent for micro-
`biologic culture. Topical
`tobrarnycin 14 mg/mL and cefazolin
`50 mg/mL were started hourly in the left eye. Both the corneal
`culture and contact lens culture subsequently grew Fusarium species.
`
`Seven days after her second flare, the corneal infiltrates had resolved
`with residual scar. Topical
`tobramycin 14 mg/mL and cefazolin
`50 mg/mL were discontinued, and the patient remained symptom-
`and recurrence free at her 1-month visit.
`
`Case 4
`
`lens
`A 40-year-old woman with a history of soft contact
`wear and Renu MoistureLoc contact lens solution use presented with
`a 4-day history of pain in her right eye. Topical moxifloxacin 0.5%
`every 2 hours in the right eye had been instituted previously.
`Best-corrected visual acuity was 20/20 in the right eye and 20/20 in
`the left eye. Slit-lamp biomicroscopy showed multiple small, raised
`epithelial infiltrates in a linear arrangement along the nasal cornea
`of the right eye. Microbiologic cultures of the cornea, contact lens
`case, and contact lens solution were obtained. Topical moxifloxacin
`0.5% was continued hourly in the right eye. Growth of Fusarium
`species was identified on corneal and contact lens cultures by day 3,
`at which point the patient was both symptomatically and clinically
`improved. Topical moxifloxacin 0.5% was continued 4 times a day,
`with near-complete resolution of the infiltrate.
`infiltrate
`However, on day 10, a new adjacent epithelial
`appeared. Topical therapy was held for 72 hours, and microbiologic
`cultures were repeated. Natamycin 5% was instituted every 2 hours
`in the right eye. The repeat cultures remained negative, and 4 days
`later, the corneal infiltrate had resolved. Topical natamycin 5% was
`continued 4 times daily in the right eye. Again at 23 days after
`the initial event, a new adjacent corneal infiltrate appeared while the
`patient was on natamycin 5% therapy. Confocal microscopy showed
`hyphal elements. Topical natamycin 5% was continued. By 6 weeks
`
`
`
`FIGURE 1. Confocal microscopy showing fungal elements.
`
`
`
`FIGURE 2. Slit-lamp photograph showing resolved central,
`midstromal infiltrate.
`
`622
`
`© 2007 Lippincott Williams & Wilkins
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`Cornea 0 Volume 26, Number 5, June 2007
`
`Contact Lens—Associated Fungal Keratitis and Fluoroquinolone
`
`
`
`FIGURE 3. Slit-lamp photograph showing multifocal stromal
`infiltrate.
`
`after initial presentation, the corneal infiltrates were replaced by cor-
`neal scarring, and topical therapy was discontinued. Final examina-
`tion 4 weeks after the completion of therapy showed an inactive scar.
`
`Case 5
`
`A 40-year-old man who wore soft contact lenses was exam-
`ined for the acute onset of decreased vision of the left eye. History
`was remarkable for Renu MoistureLoc contact lens solution use.
`
`Best-corrected visual acuity was 20/20 in the right eye and 20/60 in
`the left eye. A small, central anterior stromal infiltrate of the left
`eye was present on examination. Microbiologic cultures of the cornea
`and contact lens were obtained. Topical therapy with gatifloxacin
`0.3% was instituted every hour. Vision improved to 20/30 in the
`left eye after 3 days of therapy, with 3 small residual anterior stromal
`infiltrates. Confocal microscopy revealed fungal elements (Fig. 4).
`Corneal culture revealed Staphylococcus epidermidis and Lactoba—
`cillas species. The contact lens culture also grew both organisms,
`and Fusariam species. By 21 days after initiation of therapy, best-
`corrected visual acuity was 20/20, the infiltrate was replaced by
`faint anterior stromal scarring, and topical gatifloxacin 0.3% was
`discontinued.
`
`
`
`FIGURE 4. Confocal microscopy showing fungal elements.
`
`DISCUSSION
`
`The causative agents of keratomycosis are many,
`including Fusarium, Bipolaris, Candida, and Aspergillus
`species.3 Isolation of fungal pathogens can be difficult, and
`repeated cultures or corneal biopsy may be needed. Initial treat-
`ment of suspected filngal keratitis is typically with a polyene
`antifungal agent, preferably topical natamycin 5 mg/mL sus-
`pension or, secondarily, amphotericin B 1.5 mg/mL. The
`new azole voriconazole 10 mg/mL has also been used recently
`in these infections.12 Even with appropriate therapy, fungal
`pathogens in the cornea can be difficult to eradicate and can
`lead to a prolonged treatment course.3’11 Occasionally, tissue
`adhesive glue may be needed for corneal perforation, and
`penetrating keratoplasty may be necessary in cases of medical
`treatment failure.
`
`In contrast, we report 4 cases of fungal keratitis
`associated with soft contact lens wear in which no antifungal
`therapy was needed to achieve resolution of the infection. One
`of these cases showed an early response to topical fluoro-
`quinolone with subsequent resolution on therapy including
`tobramycin 14 mg/mL, which Chodosh et al13 showed that
`Fusarium keratitis may occasionally be responsive toward. In 1
`additional case, the keratitis responded initially without anti-
`fungal therapy but eventually required topical natamycin 5% to
`attain clearance of the filngus. Potentially, the innate immune
`response may be responsible for overwhelming relatively feeble
`strains of fiingi. Interestingly, however, all patients shared an
`initial clinical response to topical fluoroquinolone therapy.
`Fluoroquinolone
`antibacterial
`activity
`is
`realized
`through the enzymatic inhibition of type II topoisomerase
`DNA gyrase and topoisomerase IV.14 Fourth-generation
`quinolones such as moxifloxacin and gatifloxacin show
`enhanced activity against DNA gyrase.15 Fluoroquinolones
`also inhibit eukaryotic topoisomerase II, which more closely
`resembles prokaryotic topoisomerase IV in function than
`DNA gyrase. However, quinolones are nearly 1000 times
`more selective for bacterial topoisomerases than mammalian
`enzyme. 14 However, in vitro concentrations of fluoroquinolone
`clinically proven to be safe can be cytotoxic to eukaryotic cells
`when examined under in vivo conditions, showing a complex
`and as yet poorly understood interaction on the immunologic
`level.14
`The presence of DNA topoisomerases I and II has
`been confirmed in yeast cells.16 Likewise, a quinolone variant
`was shown to have enhanced DNA cleavage effect in Candida
`over mammalian cells.17 In our microbiology laboratory, we
`showed thatboth gatifloxacin 0.3% and moxifloxacin 0.5% sig-
`nificantly reduced in vitro colony counts of Candida albicans
`and Fusarium oxysporum isolates and similarly reduced
`in vivo colony count recovery in patients receiving gatifloxacin
`0.3% or moxifloxacin 0.5% treatment before cultivation
`
`(unpublished data).
`In addition, the immunomodulating effect of fluoroqui-
`nolones in fungal models has been studied. Nakajima et al18
`showed in an in vitro and in vivo model that fluoroquinolone
`can potentiate amphotericin B and fluconazole activity against
`a variety of Candida species and Cryptococcus neoformans.
`Similar synergy was shown with ofloxacin and fluconazole in
`
`© 2007 Lippincott Williams & Wilkins
`
`623
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`Munir et al
`
`Cornea 0 Volume 26, Number 5, June 2007
`
`a Candida albicans model.19 Anti-inflammatory effects with
`beneficial alterations of cytokine production have also been
`shown after quinolone use.”21 Most emphasize the need for a
`“synergistic” stress such as concurrent infection or inflam-
`mation for quinolone immunomodulation to take place.14
`Although corneal cultures were positive in 2 of the
`5 cases,
`significant clinical and laboratory evidence for
`keratomycosis existed in all patients (Table 1). All 5 patients
`exhibited growth of filngus from cultures of contact lens par-
`aphernalia. In our experience, fungus-positive contact lens
`paraphernalia correlates well with positive corneal culture.
`Our recently reported filngal keratitis series showed that 10 of
`11 contact lens cultures were positive for fungal growth, and
`all 3 contact
`lens case cultures were positive for fungal
`growth.11 A recent review of our microbiologic data also
`revealed that, of 22 consecutive contact lenses sent for culture,
`5 were positive for filngal growth. Of these 5 lens cultures,
`3 had concomitant corneal cultures, all 3 of which were posi-
`tive for fungal growth (unpublished data).
`Of the 3 cases in this series without positive corneal
`cultures, 2 patients had positive confocal microscopy and
`2 patients had multifocal infiltrates suggestive of keratomy-
`cosis. The Academy of Ophthalmology has commented on the
`use of confocal microscopy in infectious keratitis and shown that
`confocal microscopy may be used to diagnose filngal keratitis.22
`Again, in our recent series of fungal keratitis, all 5 patients who
`had confocal microscopy performed were positive.11
`All 5 patients in this series reported use of Renu
`contact lens solution. Four patients specifically confirmed the
`use of Renu MoistureLoc contact lens solution, which was
`recently pulled from the market after its implication by the
`Centers for Disease Control and Prevention in the recent
`outbreak of Fusarium keratitis.23
`
`less potent strains of fungi, or particularly
`Possibly,
`favorable innate immune responses, were responsible for the
`lack of growth on corneal microbiologic culture in the 3 cases.
`Likewise, these factors may partially explain the concomitant
`initial or complete response of the keratomycoses without
`specific antifilngal therapy. Corneal scraping for microbiologic
`culture may also have served as therapeutic debridement,
`lessening the filngal load on the cornea. Nonetheless, the role
`of fluoroquinolones as irnmunomodulatory agents in the
`presence of fungal keratitis should be explored further and
`may lead to the development of more targeted inhibition of
`filngal-specific topoisomerases.
`
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`© 2007 Lippincott Williams & Wilkins
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`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`