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The document discusses updates on the management of infectious keratitis. It covers new diagnostic techniques like in vivo confocal microscopy and next generation sequencing. It also discusses treatments for bacterial, fungal, and viral keratitis, including topical antibiotics and corticosteroids. Future strategies aim to modify the immune response to improve outcomes.
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0% found this document useful (0 votes)
26 views16 pages

Journal

The document discusses updates on the management of infectious keratitis. It covers new diagnostic techniques like in vivo confocal microscopy and next generation sequencing. It also discusses treatments for bacterial, fungal, and viral keratitis, including topical antibiotics and corticosteroids. Future strategies aim to modify the immune response to improve outcomes.
Copyright
© © All Rights Reserved
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Download as PDF, TXT or read online on Scribd
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Author manuscript
Ophthalmology. Author manuscript; available in PMC 2018 November 01.
Author Manuscript

Published in final edited form as:


Ophthalmology. 2017 November ; 124(11): 1678–1689. doi:10.1016/j.ophtha.2017.05.012.

Update on the Management of Infectious Keratitis


Ariana Austin, MS1, Tom Lietman, MD1, and Jennifer Rose-Nussbaumer, MD1,2
1
Francis I. Proctor Foundation, University of California, San Francisco
2
Department of Ophthalmology, University of California, San Francisco

Abstract
Author Manuscript

Infectious keratitis is a major global cause of visual impairment and blindness, often affecting
marginalized populations. Proper diagnosis of the causative organism is critical, and while culture
remains the prevailing diagnostic tool, newer techniques such as in vivo confocal microscopy are
helpful for diagnosing fungal keratitis and Acanthameoba. Next generation sequencing holds the
potential for early and accurate diagnosis even for organisms that are difficult to culture by
conventional methods.

Topical antibiotics remain the best treatment for bacterial keratitis, and a recent review found all
commonly prescribed topical antibiotics to be equally effective. However outcomes remain poor
secondary to corneal melting, scarring and perforation. Adjuvant therapies aimed at reducing the
immune response responsible for much of the morbidity associated with keratitis include topical
corticosteroids. The large, randomized controlled Steroids for Corneal Ulcers trial found that while
steroids provided no significant improvement overall, they did appear beneficial for ulcers that
Author Manuscript

were central, deep or large, non-Nocardia or classically invasive P. aeruginosa, patients with low
baseline vision, and when started early after the initiation of antibiotics.
Fungal ulcers often have worse clinical outcomes than bacterial ulcers, with no new treatments
since the 1960’s when topical natamycin was introduced. The randomized controlled Mycotic
Ulcer Treatment Trial showed a benefit of topical natamycin over topical voriconazole for fungal
keratitis, particularly among those caused by Fusarium. The second Mycotic Ulcer Treatment Trial
showed that oral voriconazole did not improve outcomes overall although there may have been
some effect among Fusarium ulcers. Given an increase in non-serious adverse events the authors
concluded that they could not recommend oral voriconazole at this time.
Viral keratitis differs from bacterial and fungal cases in that is often recurrent and is common in
developed countries. The first Herpetic Eye Disease Study (HEDS) showed a significant benefit of
Author Manuscript

topical corticosteroids and oral acyclovir for stromal keratitis. HEDS II showed that oral acyclovir
decreased the recurrence of any type of HSV keratitis by approximately half.

Corresponding Author: Jennifer Rose-Nussbaumer, MD, Assistant Professor, UCSF/Proctor Foundation, 513 Parnassus Ave, S334H,
San Francisco, CA 94122, (415) 502-2666.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
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Austin et al. Page 2

Future strategies to reduce the morbidity associated with infectious keratitis are likely to be
Author Manuscript

multidimensional with adjuvant therapies aimed at modifying the immune response to infection
holding the greatest potential to improve clinical outcomes.

INTRODUCTION
Corneal disease remains the leading cause of monocular blindness worldwide, especially
affecting marginalized populations.1 Corneal opacities, which are largely caused by
infectious keratitis, are the fourth leading cause of blindness globally and are responsible for
10% of avoidable visual impairment in the world’s least developed countries. 2,3
Approximately 2 million people develop a corneal ulcer every year in India alone.4,5 In the
United States infectious keratitis is often associated with contact lens wear, 6–8 but in
developing countries it is more commonly caused by ocular trauma sustained during
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agricultural work.9–12 In this review we explore the current literature and future directions of
the diagnosis and treatment of infectious keratitis.

DIAGNOSTICS
Proper diagnosis of keratitis is essential to determining treatment and achieving resolution of
infection. The mainstay in diagnosis is still Gram stain and culture of corneal samples
despite imperfect sensitivity.13–15 Gram and Giemsa stains are advantageous because they
provide instant results, with Gram stain accurately detecting causative organism 60–75% of
the time for bacterial cases and 35–90% in fungal cases. Giemsa has a sensitivity of 40–85%
for diagnosing fungal cases.16–18 Blood and chocolate agar are most commonly used to
culture bacteria, while Sabouraud’s agar or potato dextrose are best for isolating fungus, and
non-nutrient agar with Escherichia Coli overlay can be used to culture Acanthameoba.
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Thioglycollate broth is another option to identify aerobic or facultatively anaerobic bacteria,


but contaminant is a problem and often it is difficult to determine if isolated organisms are
the etiology of infection.19 Viral keratitis is diagnosed largely on clinical exam because of its
characteristic dendritic appearance,20 but PCR is sometimes used to confirm diagnosis
because of its high sensitivity.21

There is still substantial room for exploration of novel methods of diagnosing infectious
keratitis. In vivo confocal microscopy (IVCM) has grown in popularity in recent years due
to its rapidity and high sensitivity in detecting larger organisms such as filamentous fungus,
acanthamoeba, and Nocardia bacteria.22–26 Anterior segment optical coherence
tomography (AS-OCT) has been used more recently to provide an objective measure of
corneal infiltrate and/or scar size or to monitor corneal thinning during treatment. 27,28
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BACTERIAL KERATITIS
In the United States bacterial keratitis is most associated with contact lens use. 19 Severe
cases can progress rapidly, and can cause permanent vision loss requiring corneal
transplantation.

Bacterial pathogens described in the literature were responsible for a greater proportion
of keratitis than mycotic pathogens throughout various populations [11 - 13]. Bacterial
keratitis often occurs in patients with inherent ocular risk factors, such as ocular
trauma, contact lens use, or corneal disease. Bacterial keratitis often presents within an
Ophthalmology. Author manuscript; available in PMC 2018 November 01.
Austin et al. Page 3

epithelial defect with surrounding corneal infiltrate and stromal oedema [7]. Inflammation
within the anterior chamber associated with the keratitis may include a cellular reaction,
Author Manuscript

flare and/or a hypopyon. Progression of bacterial keratitis and outcome tends to relate to the
severity of the presentation as well as the potential risk factors for severe disease such as
systemic disease and previous ocular history.
Antibiotics
Topical antibiotics remain the first-line treatment for bacterial keratitis. Clinicians weigh
many factors when choosing an antibiotic regimen, including, broad-spectrum coverage,
toxicity, availability and cost, and region-specific epidemiology of pathogens and resistance
patterns. Indeed, a recent international survey of cornea specialists found that concerns over
several of these factors were predictive of antibiotic choice. 29

A recent Cochrane-style review of high quality, randomized, controlled, clinical trials on the
management of bacterial keratitis with topical antibiotics identified 16 trials comparing 2 or
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more topical antibiotics over at least 7 days. The authors found no significant difference in
the relative risk of treatment success defined as complete re-epithelialization of the cornea or
on time to cure.30 While there was an increase in the relative risk of minor adverse events
such as ocular discomfort or chemical conjunctivitis with aminoglycoside-cephalosporin
compared with fluoroquinolones, there was no difference in serious complications. 30–33,34

Although bacterial ulcers are usually responsive to treatment with available topical antibiotic
drops, an increase in the rates of antibiotic resistant infections such as methicillin resistant
Staphylococcus aureus (MRSA) in North America has caused concern. The United States
Center for Disease Control (CDC) estimates that 2 million people are infected with drug
resistant microbes each year.35 Approximately 80% of ocular isolates of MRSA in the US
have been reported to be resistant to the most commonly prescribed antibiotic class, the
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fluoroquinolones.36–38 In the Steroids for Corneal Ulcer Trial (SCUT), in-vitro susceptibility
was correlated with clinical outcomes.39,40,41 Therefore, corneal culture and sensitivity
testing is recommended for all corneal ulcers. Assessing response to treatment is critical and
if the patient appears to be worsening on treatment one can consider switching to fortified
broad-spectrum antibiotics if the initial therapy was fluoroquinolone monotherapy. On the
other hand, if initial therapy was with a broad-spectrum fortified antibiotic, toxicity from the
drops can become the most important factor impacting healing and reducing therapy is often
advised.

Even when bacterial ulcer pathogens are susceptible to available topical antibiotics, clinical
outcomes can be poor secondary to irregular astigmatism and corneal opacity. Therefore
investigating factors that mitigate the inflammatory response to infection which results in
corneal melting and subsequent scarring may be the way to have the greatest impact on
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clinical outcomes in bacterial keratitis.

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Austin et al. Page 4

Anti-collagenases
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During acute infection fibroblasts, keratocytes and other inflammatory cells secrete enzymes
such as collagenases and matrix metalloproteinases (MMPs) that are involved in protein
degradation and keratolysis. Directing therapy toward stabilization of corneal melting may
reduce the incidence of severe complications of infectious keratitis such as corneal
perforation and the need for therapeutic penetrating keratoplasty. Tetracyclines have been
shown to inhibit collagenase and have demonstrated antimetalloproteinase activity in
vitro.42–44 In one laboratory study, alkali-induced corneal ulceration in rabbits was
dramatically reduced from 85% to 9% in those randomized to high dose systemic
tetracycline administration.45 In another rabbit study, systemic doxycycline reduced the rate
of corneal perforation in pseudomonas ulcers by approximately 50%.46 Unfortunately there
are no high quality randomized controlled trials in humans to guide clinicians in the use of
adjuvant doxycycline for the treatment of corneal ulceration despite its widespread use
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among corneal specialists.

Steroids
The use of adjuvant corticosteroids has long been debated in the treatment of bacterial
keratitis.47–49 Proponents of the use of corticosteroids argue that they improve outcomes by
reducing inflammation, thereby reducing scarring, neovascularization, and stromal melt.49–
52 However, others argue that corticosteroids delay epithelial healing and may even worsen

infection.53–56

A recent Cochrane review of adjuvant topical steroids for bacterial keratitis identified four
randomized controlled trials comparing adjuvant steroids to topical antibiotics alone. 57
Three small randomized controlled trials examining the benefit of adjuvant topical steroids
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for the treatment of corneal ulcers found no difference in visual acuity outcomes or healing
times between those randomized to topical antibiotic alone versus topical antibiotic plus
topical steroid.58–60 The fourth and largest randomized controlled trial to investigate the role
of steroids in the treatment of bacterial ulcers to date was the Steroids for Corneal Ulcers
Trial (SCUT). SCUT was a randomized, double-masked, placebo-controlled clinical trial
that compared adjunctive topical corticosteroids to placebo in the treatment of bacterial
corneal ulcers.61 Five hundred study participants with culture-positive bacterial ulcers were
enrolled at Aravind Eye Hospitals in Madurai, Coimbatore, and Tirunelveli, India, the
University of California, San Francisco, and at the Dartmouth-Hitchcock Medical Center in
New Hampshire. Patients were randomized to receive either topical prednisolone sodium
phosphate 1.0% or topical placebo starting after a 48-hour course of topical moxifloxacin
0.5%.
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The authors of the Cochrane review concluded that there was not enough evidence to
support the use of adjuvant steroids, given that of the four trials reviewed only SCUT was
sufficiently powered.57 Given the findings of these subgroup analyses it is our practice to
administer adjuvant topical steroids in culture positive non-Nocardia bacterial keratitis
starting 48 hours after the administration of appropriate topical antibiotics. Confirmation of
the findings of the SCUT subgroup analysis is required with a well-designed randomized
controlled clinical trial. 73

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Austin et al. Page 5

FUNGAL KERATITIS
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Fungal ulcers often have worse outcomes than bacterial ulcers, and there is little evidence to
guide treatment.66 Fungal keratitis represents a relatively small percentage of infectious
keratitis cases in regions with temperate climates, however in tropical climates it can cause
up to 50% of infectious ulcers.66–68 Contact lens wear has been identified as a risk factor for
fungal keratitis in the United States and an outbreak of Fusarium keratitis among contact
lens wearers was related to the ReNu Moistureloc contact lens solution.69–72 There have
been no new FDA approved treatments since natamycin, a topical polyene, was introduced
in the 1960’s.

The diagnosis showing necrosis of the surface lamellae, acute inflammation, antigenic
response with immune ring formation, hypopyon, and severe uveitis. Ulcers caused by
filamentous fungi may show a gray to white infiltrate with a rough surface, and the area
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does not appear elevated above. Satellite lesions occur separately from the main lesion and
are associated with stromal microabscesses. Endothelial plaque may be seen parallel to the
ulcer74

Topical Treatments

Effective treatment with topical natamycin 5% is limited by its poor penetration into the
corneal stroma.73 Topical amphotericin B 0.3% to 0.5% is an alternative, but its use requires
access to a compounding pharmacy and is limited by toxicity. Voriconazole, a newer
generation triazole, has gained popularity in the treatment of fungal keratitis due to its
excellent ocular penetration.74 In addition, in one in vitro study, voriconazole was the only
drug tested in which 100% of fungal isolates commonly implicated in keratitis were
susceptible.75 Voriconazole is a proposed third option, however, the ‘Mycotic Ulcer
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Treatment Trial I’ found that voriconazole was inferior to natamycin in the treatment of all
fungal keratitis, especially Fusarium keratitis. The results of MUTT I show a benefit of
natamycin over voriconazole for topical treatment of fungal keratitis, and in particular for
Fusarium keratitis. These results have been confirmed by a second randomized clinical
trial77 and a recent Cochrane review.78
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Austin et al. Page 6

Oral Voriconazole
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Although topical voriconazole failed to show improved outcomes compared with natamycin,
there are several reasons that oral voriconazole may have efficacy in the treatment of fungal
keratitis. First, intermittent dosing of topical medications may result in intervals of sub-
therapeutic drug levels and oral medications may provide more steady-state drug levels at
the site of infection. One study comparing aqueous samples after topical and oral
voriconazole found that topical administration of voriconazole resulted in highly variable
aqueous concentrations with troughs well below the MIC90 for most fungi while oral
voriconazole provided therapeutic drug level that remained relatively constant.79 Of note, in
many case reports of successful treatment with topical voriconazole, oral and/or intravenous
voriconazole was used in conjunction with the topical medication.80,81

A subsequent subgroup analysis did find a possible benefit to oral voriconazole in Fusiarum
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ulcers.82 Other potential adjuvant treatments for fungal keratitis include intracameral
injection of amphotericin with or without hypopyon drainage 83–86,87 or intrastromal
injection of voriconazole.88–90 However, more study of these techniques with well-designed
randomized controlled trials is necessary to determine their benefit. Therefore, at this time,
topical natamycin remains the most evidence-based treatment for filamentous fungal
keratitis and oral voriconazole should be considered if the organism is Fusarium.

VIRAL KERATITIS
Herpes simplex virus (HSV) keratitis affects an estimated 500,000 people in the United
States and an estimated 1.5 million globally. 91 It is the most common cause of unilateral
infectious corneal blindness in much of the developed world. 92 Viral keratitis differs from
bacterial and fungal keratitis in that it can become chronic and recurrent. Besides being a
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painful, sight-threatening infection, HSV keratitis has been shown to significantly impact
quality of life even when patients are not experiencing an active infection.93 Less common
forms of viral keratitis include varicella-zoster virus (VZV) keratitis, and cytomegalovirus
(CMV) keratitis.

Patients with HSV keratitis complain of pain, photophobia, blurred vision, watery eyes, red
eyes, decreased visual acuity, especially if the center is affected. Primary herpes simplex
infection of the eye is usually an acute follicular conjunctivitis with ulcerative vesicular
blepharitis and regional lymph node swelling. Most patients also have epithelial keratitis
and may involve the stroma but rarely. Basically, this primary infection can heal itself, but
in certain circumstances where the body's immune system is very weak it will become
severe and attack the stroma.
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Austin et al. Page 7

Topical Treatments
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Topical treatments for viral keratitis include antiviral medications and adjuvant topical
corticosteroids. The topical antiviral trifluridine is the most commonly prescribed topical
antiviral medication for HSV keratitis in the United States.94 While it is effective in treating
HSV keratitis, it has low bioavailability and causes ocular surface toxicity, so its use has
become more limited as newer topical antivirals are developed.95 Topical acyclovir is the
first line treatment for HSV keratitis in Europe as it has been shown to be just as effective as
trifluridine with less ocular surface toxicity. Unfortunately, it is unavailable in the United
States. Ganciclovir is a newer synthetic medication with more broad-spectrum antiviral
coverage. In addition to treating HSV and VZV keratitis, topical ganciclovir is also effective
in treating keratitis caused by CMV.96 Ganciclovir has been shown to be just as effective as
acyclovir, while causing less ocular toxicity. It may also be less likely to promote drug
resistance.96,97 Northwestern University is currently conducting a large randomized
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controlled trial investigating ganciclovir for the treatment of VZV keratitis (NCT02382588).

Topical corticosteroids are also sometimes used as adjuvant therapy to topical antivirals. The
Herpetic Eye Disease Study I (HEDS I) evaluated the effectiveness of corticosteroids in
treating HSV stromal keratitis. In this randomized controlled trial 106 patients with active
HSV stromal keratitis were randomized to receive either topical prednisolone phosphate or
placebo, tapered over a 10 week period. All patients received topical trifluridine. HEDS I
found that the median time to treatment failure was drastically shorter in the placebo group:
17 days in the placebo group and 98 days in the topical steroids group ( P<0.001).98 Time to
resolution of infection was significantly shorter in the group receiving topical
corticosteroids, with a median of 26 days for those taking corticosteroids and 72 days for
those taking placebo (P<0.001). Visual acuity at 6 months was similar across groups.
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Oral Treatments
The HEDS I trial also investigated adjuvant oral acyclovir as a treatment for HSV stromal
keratitis. One hundred and four patients receiving both topical trifluridine and
corticosteroids were randomized to receive 200mg oral acyclovir or placebo, to be taken 5
times daily for 10 weeks.99 Although the investigators found that oral acyclovir delayed
treatment failure (from 62 days in the placebo group to 84 days in the acyclovir group), this
result was not statistically significant (P=0.46). Oral acyclovir did result in a statistically
significant improvement in BSCVA at 6 months (P=0.04) but the importance of this result is
hard to determine given that there was a relatively large difference in baseline BSCVA
between groups. Oral acyclovir has also been shown to be efficacious against VZV keratitis
and the results of HEDS I are often applied similarly to its treatment.
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Austin et al. Page 8

Valacyclovir, a newer antiviral, is well tolerated and there is some evidence that it may have
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better ocular penetration.100,101 Additionally, the treatment dose for valacyclovir is 1g three
times daily, as opposed to acyclovir which is 400mg five times daily (800mg five times daily
for VZV), which aids in patient compliance. Oral valganciclovir is the preferred treatment
for CMV stromal keratitis, but it has significant side effects, including aplastic anemia,
which must be closely monitored.102

In our practice we generally use oral antivirals to avoid ocular toxicity that can complicate
topical therapy and obscure the clinical picture. We reserve topical medications for adjuvant
treatment when oral medications are not adequate or in patients who are not good candidates
for systemic therapy.

Prophylaxis
HEDS II examined the prolonged use of oral acyclovir for recurrent ocular HSV. This large,
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multi-center, randomized, placebo-controlled trial, found that ocular HSV recurrence was
45% lower in the acyclovir group, with 19% in the acyclovir group experiencing recurrence
and 32% in the placebo group experiencing recurrence by 12 months ( P<0.001).103

Herpes zoster ophthalmicus (HZO) is caused by reactivation of VZV after a primary


infection. Since the introduction of routine varicella vaccination in children there has been
an increased incidence of HZO which has been attributed to a lack of passive natural
immune boost against the virus.104 At this time the recommendation is to vaccinate all older
adults with the zoster vaccine to prevent HZO and other zoster infections. The Zoster Eye
Disease Study will investigate the extended use of oral valacyclovir for the prophylaxis of
VZV keratitis.
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CONCLUSION
Despite having appropriate antimicrobial treatments for most of the pathogens implicated in
infectious keratitis, clinical outcomes are often poor. Strategies to reduce the morbidity
associated with this condition are likely going to have to be multidimensional involving
corneal ulcer prevention, improved early and accurate diagnostics techniques such as next
generation sequencing as well as novel antimicrobial agents to address the development of
drug resistance. Adjuvant therapies that focus on modifying the immune response to the
infection thereby reducing the corneal melting and scarring which ultimately leads to poor
vision, may have the greatest potential to improve clinical outcomes.

The prevention of Acanthamoeba keratitis prioritises the strict and appropriate use of
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contact lenses. Contact lenses must be cleaned and stored in appropriate disinfecting
solutions and avoid exposure to potentially contaminated water supplies.

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Austin et al. Page 10

Acknowledgments
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There are no conflicts of interest to declare. Individual support for this study came from K23 EY025025 (JRN), an
unrestricted grant from the Peirles Foundation (JRN), and an unrestricted grant from Research to Prevent Blindness
(JRN).

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