Is there a preference between topical natamycin and topical voriconazole for first-line treatment of fungal keratitis?

Introduction
Fungal keratitis is an infection of the cornea caused by fungi that invades, attaches, and grows within the eye.1,2 Worldwide infection rates have been increasing.3 In the United States, fungal keratitis accounts for 5% to 10% of all corneal infections, which is less than bacterial and viral keratitis.1 Contact lens use has resulted in an increased incidence of infections since the mid-2000s. Developing countries and geographic locations with warmer and humid environments tend to have higher rates of fungal keratitis.1,2 Fungal keratitis tends to be slowly progressive and insidious as the host’s inflammatory response leads to inflammatory cell infiltration, necrosis, and neovascularization. Untreated infections can ultimately lead to irreversible vision loss.3 The clinical presentation includes satellite lesions, dry gray elevated infiltrates with feathery edges, and less inflammation than bacterial keratitis. Severe cases exhibit larger lesions accompanied by endothelial plaques or hypopyons. The most common fungal keratitis pathogens include filamentous fungi (eg. Fusarium and Aspergillus species) which are often found in tropical climates, and Candida species in temperate environments.1 Filamentous fungi and yeasts are also the most common species found in patients wearing contact lenses.4 Other less common pathogens include Curvularia, Paecilomyces, Phialaphora, Blastomyces, Sporothrix, and Exophiala species.1

Topical antifungal therapeutic options are currently limited due to challenges in creating formulations that are efficacious in the eye.1,2 Current treatments include natamycin 5%, voriconazole 1%, and amphotericin B 0.15% solution or 5% suspension. Natamycin is the only US Food and Drug Administration (FDA) approved and commercially available topical antifungal for ophthalmic use; topical voriconazole and amphotericin B must be extemporaneously compounded.1,5 Natamycin has broad coverage against filamentous fungi and yeasts.2 Voriconazole has good activity against yeasts but has varying filamentous organism coverage. Amphotericin B has good activity against yeasts but is not appropriate for filamentous organisms (eg, Aspergillus species). Amphotericin B is recommended for keratitis caused by Candida and is an alternative to natamycin for other non-filamentous pathogens.1,2,6 Only 1 small, underpowered study has compared the efficacy of natamycin and amphotericin B so the comparative efficacy between these 2 agents remains an area of future study.7

Tertiary resources recommend using natamycin as a first-line treatment option because of improved outcomes compared to voriconazole.1,2,6,8 Since no guidelines currently exist, there is diversity in medication usage in practice and both natamycin and voriconazole are used first-line.4,9 One commonly cited protocol recommends initiating therapy with topical natamycin.10 Voriconazole 200 mg orally once daily may be added to natamycin for ulcers with a diameter of 0.5 mm and/or depth of 50%. Topical voriconazole can be added after 7 to 10 days if natamycin therapy is unsuccessful. Surgical intervention (such as therapeutic keratoplasty) may be necessary for severe infections with ulcer perforations greater than 2 mm, or when no improvement is observed with pharmacological therapy.2,3

Due to the sight-threatening nature of this infection, there is a need to define optimal first-line treatment. This article will summarize the comparative efficacy data with topical natamycin and topical voriconazole for fungal keratitis first-line treatment.

Literature review

A 2015 meta-analysis included 3 randomized controlled trials (RCTs) that compared topical natamycin and topical voriconazole.11 Conclusions could not be made about clinical cure or microbiological cure since only one trial assessed each of these outcomes. Based on data from all 3 trials, visual acuity at 2 to 3 months was similar with both treatments but risk of corneal perforation/therapeutic penetrating keratoplasty was lower with natamycin (risk ratio, 0.61; 95% confidence interval [CI], 0.40 to 0.94; high quality evidence). Another meta-analysis of 3 RCTs found no difference in treatment failure or corneal perforation between natamycin and voriconazole; however, therapeutic keratoplasty was more likely with voriconazole (relative risk, 1.89; 95% CI, 1.14 to 3.12).12 Final visual acuity was significantly better with natamycin (p=0.05).

The currently available RCTs with topical natamycin and topical voriconazole for fungal keratitis are summarized in the Table.13-18 In addition to the 3 studies included in the meta-analyses (Prajna 2010, Arora 2011, Prajna 2013), there is one more recent study and one study that used topical therapy combined with oral voriconazole.

Table. Comparative studies of topical natamycin and topical voriconazole for fungal keratitis.13-18
Study and  design
Subjects and location
 
Interventions
Results
Conclusions
Sharma 201513
 
RCT
N=118 patients with fungal keratitis
 
Fusarium (25%), Aspergillus (13%), other filamentous fungi (36%)
 
3 centers in India
Natamycin 5%
 
Voriconazole 1%
 
Topically every hour for 3 days, every hour while awake and every 3 hours while asleep on day 4, then 1 drop every 2 hours while awake until cured
Healed or resolving ulcer: natamycin 89.2% vs. voriconazole 66.6% (p=0.005)
 
Visual acuity: better with natamycin vs. voriconazole (p=0.01), especially among patients with Fusarium infections
Natamycin was more effective, especially in patients with Fusarium infections.
Prajna 201314 (MUTT I)
 
RCT
N=323 patients with smear-positive filamentous fungal ulcer and decreased visual acuity
 
Fusarium (40%), Aspergillus (17%), other filamentous fungi (43%)
 
3 centers in India
Natamycin 5%
 
Voriconazole 1%
 
Topically every hour while awake for 1 week, then every 2 hours while awake for 2 weeks
Visual acuity at 3 months: better with natamycin vs. voriconazole (p=0.006); patients with Fusarium infections were more likely to improve with natamycin than voriconazole (p<0.001); outcomes were similar for non-Fusarium infections (p=0.81)
 
Corneal perforation or need for therapeutic penetrating keratoplasty: lower with natamycin vs. voriconazole (p=0.009)
Natamycin led to better clinical and microbiological outcomes, especially for Fusarium infections.
Parchand 201215
 
RCT
N=30 patients with severe fungal corneal ulcer
 
Fusarium (13.3%), Aspergillus (17.7%)
 
1 center in India
Oral voriconazole + topical natamycin 5%
 
Oral voriconazole + topical voriconazole 1%
 
Dosing schedule not specified
Time to resolution: similar between groups
 
Visual acuity at 3 months: similar between groups
Larger studies comparing these treatments are needed.
Arora 201116
 
RCT
N=30 patients with fungal corneal ulcer
 
Fusarium (10%), Aspergillus (40%), Curvularia (30%)
 
1 center in India
Natamycin 5%
 
Voriconazole 1%
 
Topically every hour for 2 weeks
Time to resolution: natamycin 24.33 days vs. voriconazole 27.42 days (p>0.05)
 
Visual acuity: similar in both groups (p=0.227)
Study may have been underpowered to detect differences between groups.
Prajna 201017,18
 
RCT
N=120 patients with fungal corneal ulcer
 
Fusarium (37%), Aspergillus (16%), other filamentous fungi (32%)
 
2 centers in India
Natamycin 5%
 
Voriconazole 1%
 
Topically every hour while awake for 1 week, then every 2 hours while awake for 2 weeks
Visual acuity at 3 months: similar between groups (p=0.29)
 
Corneal perforation: 9 natamycin, 10 voriconazole (p>0.99)
 
Subgroup analysis (Fusarium infections):
Similar visual acuity at 3 months between treatments (p=0.54), higher risk of corneal perforation with voriconazole (p=0.041)
 
Subgroup analysis (Aspergillus infections):
Similar visual acuity (p=0.38) and corneal perforation (p=0.44) in both groups
There were no differences in visual acuity between groups. Healing was not assessed.
Abbreviations: MUTT=Mycotic Ulcer Treatment Trial; RCT=randomized controlled trial.

Conclusion
Several randomized trials and meta-analyses have compared topical natamycin and topical voriconazole for initial treatment of fungal keratitis. Multiple analyses suggest that natamycin is more effective than voriconazole, especially in patients with Fusarium infections, for healing, improvement in visual acuity, and decreasing the need for surgical intervention. Natamycin also has the clinical advantage of commercial availability and FDA approval for keratitis. To promote more consistent first-line use of natamycin in the United States, larger and more geographically representative studies may be needed.

References

  1. Azar DT, Halak J, Barnes S, Giri P, Pavan-Langston D. Microbial keratitis. In: Bennett J, Dolin R, Blaser M, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 9th Elsevier, Inc; 2020:1508-1522.
  2. Keenan JD, McLeod SD. Fungal keratitis. In: Yanoff M, Duker J, eds. Ophthalmology. 6th ed. Elsevier, Inc. 2023:204-206
  3. Reginatto P, Agostinetto GJ, Fuentefria RDN, Marinho DR, Pizzol MD, Fuentefria AM. Eye fungal infections: a mini review. Arch Microbiol. 2023;205-236. doi:10.1007/s00203-023-03536-6
  4. Gower EW, Keay LJ, Oechsler RA, et al. Trends in fungal keratitis in the United States, 2001 to 2007. Ophthalmology. 2010;117(12):2263-2267. doi:10.1016/j.ophtha.2010.03.048
  5. Prajna NV, Krishnan T, Mascarenhas J, et al. The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013;131(4):422-429. doi:10.1001/jamaophthalmol.2013.1497
  6. Gilbert D, Chambers H, Saag M, et al. The Sanford Guide to Antimicrobial Therapy 2021. 51st ed. Antimicrobial Therapy, Inc; 2021.
  7. Prajna NV, Radhakrishnan N, Lalitha P, et al. Cross-linking-assisted infection reduction: a randomized clinical trial evaluating the effect of adjuvant cross-linking on outcomes in fungal keratitis. Ophthalmology. 2020;127(2):159-166. doi:10.1016/j.ophtha.2019.08.029
  8. Nucci M. Treatment and prevention of Fusarium infection. In: Kauffman C, ed. UpToDate. Wolters Kluwer; 2023. Accessed July 12, 2023. https://www.uptodate.com/contents/treatment-and-prevention-of-fusarium-infection?search=fungal%20keratitis&source=search_result&selectedTitle=1~27&usage_type=default&display_rank=1
  9. Atta S, Perera C, Kowalski RP, Jhanji V. Fungal keratitis: clinical features, risk factors, treatment, and outcomes. J Fungi (Basel). 2022;8(9):962. doi:10.3390/jof8090962
  10. Sharma, N, Sahay P, Maharana P, et al. Management algorithm for fungal keratitis: the TST (topical, systemic, and targeted therapy) protocol. Cornea. 2019;38(2):141-145. doi:10.1097/ICO.0000000000001781
  11. FlorCruz NV, Evans JR. Medical interventions for fungal keratitis. Cochrane Database Syst Rev. 2015;(4):CD004241. doi:10.1002/14651858.CD004241.pub4
  12. McDonald EM, Ram FS, Patel DV, McGhee CN. Effectiveness of topical antifungal drugs in the management of fungal keratitis: a systematic review and meta-analysis of randomized controlled trials. Asia Pac J Ophthalmol (Phila). 2014;3(1):41-47. doi:10.1097/APO.0b013e3182a618dd
  13. Sharma S, Das S, Virdi A, et al. Re-appraisal of topical 1% voriconazole and 5% natamycin in the treatment of fungal keratitis in a randomised trial. Br J Ophthalmol. 2015;99(9):1190-1195. doi:10.1136/bjophthalmol-2014-306485
  14. Prajna NV, Krishnan T, Mascarenhas J, et al. The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013;131(4):422-429. doi:10.1001/jamaophthalmol.2013.1497
  15. Parchand S, Gupta A, Ram J, Gupta N, Chakrabarty A. Voriconazole for fungal corneal ulcers. Ophthalmology. 2012;119(5):1083. doi:10.1016/j.ophtha.2011.11.034
  16. Arora R, Gupta D, Goyal J, Kaur R. Voriconazole versus natamycin as primary treatment in fungal corneal ulcers. Clin Exp Ophthalmol. 2011;39(5):434-440. doi:10.1111/j.1442-9071.2010.02473.x
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  18. Prajna VN, Lalitha PS, Mascarenhas J, et al. Natamycin and voriconazole in Fusarium and Aspergillus keratitis: subgroup analysis of a randomised controlled trial. Br J Ophthalmol. 2012;96(11):1440-1441. doi:10.1136/bjophthalmol-2012-301825

Prepared by:
Gunjan Patel
PharmD Candidate Class of 2024
University of Illinois Chicago College of Pharmacy

Heather Ipema, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois Chicago College of Pharmacy

August 2023

The information presented is current as of July 7, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.