Fungal keratitis

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Summary of Evidence

Antifungal choice

Natamycin was associated with significantly better clinical outcomes than voriconazole for filamentous fungal keratitis, especially in Fusarium cases; Do not use voriconazole as monotherapy in filamentous keratitis.(MUTT, 2013) {Prajna NV, Krishnan T, Mascarenhas J, Rajaraman R, Prajna L, Srinivasan M, Raghavan A, Oldenburg CE, Ray KJ, Zegans ME, McLeod SD, Porco TC, Acharya NR, Lietman TM; Mycotic Ulcer Treatment Trial Group. The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013 Apr;131(4):422-9.}

 

There was no benefit (rate of corneal perforation/need for PK) to adding oral voriconazole to topical antifungal eyedrops in the treatment of severe filamentous fungal ulcers.(MUTT II, 2016){Prajna NV, Krishnan T, Rajaraman R, Patel S, Srinivasan M, Das M, Ray KJ, O’Brien KS, Oldenburg CE, McLeod SD, Zegans ME, Porco TC, Acharya NR, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial II Group. Effect of Oral Voriconazole on Fungal Keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II): A Randomized Clinical Trial. JAMA Ophthalmol. 2016 Dec 1;134(12):1365-1372.}

 

In a secondary analysis of visual outcomes in subgroup with Fusarium ulcers (at 3 months) in the MUTT II trial, Fusarium keratitis may benefit (decreased risk of perforation or need for PK) from the addition of oral voriconazole to topical natamycin.(MUTT II, 2017) {Prajna NV, Krishnan T, Rajaraman R, Patel S, Shah R, Srinivasan M, Devi L, Das M, Ray KJ, O’Brien KS, Oldenburg CE, McLeod SD, Zegans ME, Acharya NR, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial Group. Adjunctive Oral Voriconazole Treatment of Fusarium Keratitis: A Secondary Analysis From the Mycotic Ulcer Treatment Trial II. JAMA Ophthalmol. 2017 Jun 1;135(6):520-525.}

Corneal collagen cross-linking

There appears to be no benefit of adjuvant corneal crosslinking in the primary treatment of moderate filamentous fungal ulcers, and it may result in decreased visual acuity. {Prajna NV, Radhakrishnan N, Lalitha P, Austin A, Ray KJ, Keenan JD, Porco TC, Lietman TM, Rose-Nussbaumer J. Cross-Linking-Assisted Infection Reduction: A Randomized Clinical Trial Evaluating the Effect of Adjuvant Cross-Linking on Outcomes in Fungal Keratitis. Ophthalmology. 2020 Feb;127(2):159-166.}

Evidence

1. Risk factors

1.1 Contact lens wear

Review

2017 Kam et.al.

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2017
Review

The majority of infections in association with orthokeratology lens wear resulted in the formation of corneal scars and almost 10% of eyes needed surgical treatment. {Kam KW, Yung W, Li GKH, Chen LJ, Young AL. Infectious keratitis and orthokeratology lens use: a systematic review. Infection. 2017 Dec;45(6):727-735.}

  • Analysis of 29 articles involving 173 eyes of infectious keratitis in association with orthokeratology lens wear
  • Findings:
    • Mean age at presentation: 15.4 years
    • male-to-female ratio 1:1.7
    • positive microbiological cultures reported in 69.4% of cases
    • Pseudomonas aeruginosa and Acanthamoeba were the most common etiological agents
    • mean duration of hospitalization 7.7 days
    • LogMAR VA improved from 1.17 to 0.33 from presentation to final visit

2. Treatment

2.1 Antifungal choice

Clinical Trial

2017 Prajna et.al. (MUTT II)

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2017
Clinical Trial

In a secondary analysis of visual outcomes in subgroup with Fusarium ulcers (at 3 months) in the MUTT II trial, Fusarium keratitis may benefit (decreased risk of perforation or need for PK) from the addition of oral voriconazole to topical natamycin. {Prajna NV, Krishnan T, Rajaraman R, Patel S, Shah R, Srinivasan M, Devi L, Das M, Ray KJ, O’Brien KS, Oldenburg CE, McLeod SD, Zegans ME, Acharya NR, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial Group. Adjunctive Oral Voriconazole Treatment of Fusarium Keratitis: A Secondary Analysis From the Mycotic Ulcer Treatment Trial II. JAMA Ophthalmol. 2017 Jun 1;135(6):520-525.}

  • Randomized controlled trial of topical antifungals and either oral voriconazole vs placebo in patients with filamentous fungal ulcer (n=318)
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Clinical Trial

2016 Prajna et.al. (MUTT II)

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2016
Clinical Trial

There was no benefit (rate of corneal perforation/need for PK) to adding oral voriconazole to topical antifungal eyedrops in the treatment of severe filamentous fungal ulcers. {Prajna NV, Krishnan T, Rajaraman R, Patel S, Srinivasan M, Das M, Ray KJ, O’Brien KS, Oldenburg CE, McLeod SD, Zegans ME, Porco TC, Acharya NR, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial II Group. Effect of Oral Voriconazole on Fungal Keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II): A Randomized Clinical Trial. JAMA Ophthalmol. 2016 Dec 1;134(12):1365-1372.}

  • Randomized controlled trial of topical antifungals and either oral voriconazole vs placebo in patients with filamentous fungal ulcer (n=318)
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Review

2015 FlorCruz and Evans (Cochrane)

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2015
Review

Analysis of 12 trials concluded there is evidence natamycin is more effective than voriconazole in the treatment of fungal ulcers. {FlorCruz NV, Evans JR. Medical interventions for fungal keratitis. Cochrane Database Syst Rev. 2015 Apr 9;(4):CD004241.}

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Clinical Trial

2013 Prajna et.al. (MUTT)

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2013
Clinical Trial

Natamycin was associated with significantly better clinical outcomes than voriconazole for filamentous fungal keratitis, especially in Fusarium cases; Do not use voriconazole as monotherapy in filamentous keratitis. {Prajna NV, Krishnan T, Mascarenhas J, Rajaraman R, Prajna L, Srinivasan M, Raghavan A, Oldenburg CE, Ray KJ, Zegans ME, McLeod SD, Porco TC, Acharya NR, Lietman TM; Mycotic Ulcer Treatment Trial Group. The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013 Apr;131(4):422-9.}

  • Randomized controlled trial of topical voriconazole 1% vs topical natamycin 5% in patients with Filamentous fungal ulcer (n=323).
  • Findings
    • Natamycin-treated cases had significantly better BCVA, decreased risk of perforation or need for therapeutic penetrating keratoplasty.
    • Fusarium cases on natamycin had better visual outcomes but similar risk of perforation
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2.2 Fungal cultures

Clinical Trial

2018 Prajna et.al. (MUTT II)

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2018
Clinical Trial

Day 6 culture results can be used to assess response to medical therapy and identify patients who are at high risk of a poor clinical outcome (corneal perforation or need for therapeutic penetrating keratoplasty). {Ray KJ, Prajna NV, Lalitha P, Rajaraman R, Krishnan T, Patel S, Das M, Shah R, Dhakhwa K, McLeod SD, Zegans ME, Acharya NR, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial Group. The Significance of Repeat Cultures in the Treatment of Severe Fungal Keratitis. Am J Ophthalmol. 2018 May;189:41-46.}

  • Secondary analysis of trial data of patients presenting with a smear-positive filamentous fungal ulcer and VA ≤ 20/400 who subsequently had a 6-day fungal culture performed
  • Results
    • Patients who tested positive at their 6-day culture had twice the hazard of experiencing a corneal perforation or the need for therapeutic penetrating keratoplasty than those who tested negative, even after controlling for baseline ulcer characteristics
    • Positive patients also had 0.26 logMAR lines worse VA at 3 months
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2.3 Corneal crosslinking

Clinical Trial

2020 Prajna et.al.

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2020
Clinical Trial

There appears to be no benefit of adjuvant corneal crosslinking in the primary treatment of moderate filamentous fungal ulcers, and it may result in decreased visual acuity. {Prajna NV, Radhakrishnan N, Lalitha P, Austin A, Ray KJ, Keenan JD, Porco TC, Lietman TM, Rose-Nussbaumer J. Cross-Linking-Assisted Infection Reduction: A Randomized Clinical Trial Evaluating the Effect of Adjuvant Cross-Linking on Outcomes in Fungal Keratitis. Ophthalmology. 2020 Feb;127(2):159-166.}

  • Randomized controlled trial of 4 treatment combinations (111 patients):

topical natamycin 5%  topical natamycin 5% + CXL  topical amphotericin B 0.15%  topical amphotericin B 0.15% + CXL

  • Findings
    • Primary Outcome measure (microbiological cure at 24 hours on repeat culture)
      • No statistically significant difference in 24-hour culture positivity between groups, although those randomized to CXL had 1.32-fold increased odds of 24-hour culture positivity.
    • Secondary outcome measure (BCVA at 3 weeks and 3 months)
      • BCVA 0.22 LogMAR (2.2 Snellen lines) worse at 3 weeks and 0.32 LogMAR (3.2 Snellen lines) worse at 3 months in those receiving CXL regardless of medication.
      • There was no difference in infiltrate/scar size, percentage of epithelialized or adverse events between groups
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Clinical Trial

2019 Wei et.al.

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2019
Clinical Trial

Adjuvant corneal cross-linking accelerated healing of fungal ulcers, shortened the treatment duration, and minimized the need for medications and surgery in a randomized controlled trial of 41 patients with fungal keratitis treated with antifungal medications or antifungal medications alone. {Wei A, Wang K, Wang Y, Gong L, Xu J, Shao T. Evaluation of corneal cross-linking as adjuvant therapy for the management of fungal keratitis. Graefes Arch Clin Exp Ophthalmol. 2019 Jul;257(7):1443-1452.}

  • Randomized controlled trial of 4 treatment combinations:

topical natamycin 5%    topical natamycin 5% + CXL    topical amphotericin B 0.15%    topical amphotericin B 0.15% + CXL

  • Findings
    • Primary Outcome measure (microbiological cure at 24 hours on repeat culture)
      • No statistically significant difference in 24-hour culture positivity between groups, although those randomized to CXL had 1.32-fold increased odds of 24-hour culture positivity.
    • Secondary outcome measure (BCVA at 3 weeks and 3 months)
      • BCVA 0.22 LogMAR (2.2 Snellen lines) worse at 3 weeks and 0.32 LogMAR (3.2 Snellen lines) worse at 3 months in those receiving CXL regardless of medication.
      • There was no difference in infiltrate/scar size, percentage of epithelialized or adverse events between groups

3. Prognosis

Cohort study

2019 Prajna et.al.

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2019
Cohort study

Best-corrected vision (spectacle/contact lens) in the better eye was worse than 20/60 in 10 individuals (20.0%) in the bacterial ulcer group four years after treatment for keratitis. {Prajna NV, Srinivasan M, Mascarenhas J, Lalitha P, Rajaraman R, McClintic SM, O’Brien KS, Ray KJ, Acharya NR, Lietman TM, Keenan JD. Visual Impairment in Fungal Versus Bacterial Corneal Ulcers 4 Years After Successful Antimicrobial Treatment. Am J Ophthalmol. 2019 Aug;204:124-129.}

  • Prospective cohort study of 100 individuals with fungal or bacterial keratitis diagnosed 4 years prior
  • Findings:
    • Long-term visual outcomes were similar between fungal and bacterial ulcers, although fungal ulcers were more likely to produce severe visual impairment. (BCVA worse than 20/60 24% vs 20%)
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References

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