The Mycotic Ulcer Treatment Trial A Randomized Trial Comparing Natamycin vs Voriconazole

Archives of ophthalmology (Impact Factor: 4.49). 12/2012; 131(4):1-8. DOI: 10.1001/jamaophthalmol.2013.1497
Source: PubMed

ABSTRACT Objective: To compare topical natamycin vs voriconazole in the treatment of filamentous fungal keratitis. Methods: This phase 3, double-masked, multicenter trial was designed to randomize 368 patients to voriconazole (1%) or natamycin (5%), applied topically every hour while awake until reepithelialization, then 4 times daily for at least 3 weeks. Eligibility included smear-positive filamentous fungal ulcer and visual acuity of 20/40 to 20/400. Main Outcome Measures: The primary outcome was best spectacle-corrected visual acuity at 3 months; secondary outcomes included corneal perforation and/or therapeutic penetrating keratoplasty. Results: A total of 940 patients were screened and 323 were enrolled. Causative organisms included Fusarium (128 patients [40%]), Aspergillus (54 patients [17%]), and other filamentous fungi (141 patients [43%]). Natamycin-treated cases had significantly better 3-month best spectacle-corrected visual acuity than voriconazole-treated cases (regression coefficient = -0.18 logMAR; 95% CI, -0.30 to -0.05; P = .006). Natamycin-treated cases were less likely to have perforation or require therapeutic penetrating keratoplasty (odds ratio = 0.42; 95% CI, 0.22 to 0.80; P = .009). Fusarium cases fared better with natamycin than with voriconazole (regression coefficient= -0.41 logMAR; 95% CI, -0.61 to -0.20; P < .001; odds ratio for perforation = 0.06; 95% CI, 0.01 to 0.28; P < .001), while non-Fusarium cases fared similarly (regression coefficient = -0.02 logMAR; 95% CI, -0.17 to 0.13; P = .81; odds ratio for perforation = 1.08; 95% CI, 0.48 to 2.43; P =. 86). Conclusions: Natamycin treatment was associated with significantly better clinical and microbiological outcomes than voriconazole treatment for smear-positive filamentous fungal keratitis, with much of the difference attributable to improved results in Fusarium cases. Application to Clinical Practice: Voriconazole should not be used as monotherapy in filamentous keratitis.

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    • "Cultures used in this study were obtained from keratitis patients attending Aravind Eye Hospital, Madurai. Corneal scrapings from infected patients were spread on potato dextrose agar and fungal positive plates were used for routine laboratory identifications based on colony morphology and microscopic identification as described previously [21]. Genomic DNA was extracted from fungal mat and used for amplification of the ITS region. "
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    ABSTRACT: Aspergillus flavus infects the human eye leading to keratitis. Extracellular proteins, the earliest proteins that come in contact with the host and virulence related exoproteins, were identified in the fungus isolated from infected cornea. Virulence of the corneal isolates was tested in the Galleria mellonella larvae model and those isolates showing higher virulence were taken for subsequent exoproteome analysis. High resolution two-dimensional electrophoresis and mass spectrometry were used to generate A. flavus exoproteome reference map as well as to profile most of the exoproteins. Analysis of the identified proteins clearly shows the major biological processes that they are involved in. Nearly 50% of the exoproteins possess catalytic activity and one of these, an alkaline serine protease (Alp1) is present in high abundance as well as multiple proteoforms. Many proteins in the A. flavus exoproteome have been shown to be virulence factors in other pathogens indicating the probable role for these proteins in the corneal infection as well. Interestingly, the majority of the exoproteins do not have secretory signal indicating that they are secreted through the non-classical pathway. Thus, this study provides a clue to the early strategies employed by the pathogen to establish an infection in an immunocompetent host.
    Journal of Proteomics 12/2014; 115. DOI:10.1016/j.jprot.2014.11.017 · 3.93 Impact Factor
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    • "Spreading stock solutions (0.5 mg/mL) for the lipids were made daily by dissolving each compound separately in chloroform, with mixtures being produced in the desired proportions. Aqueous solution/suspension of natamycin is quite stable [15], which is why aqueous formulations are used in therapeutic applications [20] [21] [22] and as food additives [16] [17] [18]. In ultrapure water (pH = 5.5–6) natamycin molecules are slightly positively charged, since their isoelectric point is at pH = 6.5 [15] [35]. "
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    ABSTRACT: Natamycin is an effective, broad spectrum antifungal with no reported resistance, in contrast to most antimicrobials. It also exhibits reduced (oral and topical) toxicity to humans, which is probably associated with the lack of effects on mammalian cell membranes. In this paper we employ Langmuir monolayers to mimic a cell membrane, whose properties are interrogated with various techniques. We found that natamycin has negligible effects on Langmuir monolayers of dipalmitoyl phosphatidylcholine (DPPC), but it strongly affects cholesterol monolayers. Natamycin causes the surface pressure isotherm of a cholesterol monolayer to expand even at high surface pressures since it penetrates into the hydrophobic chains. It also reduces the compressibility modulus, probably because natamycin disturbs the organization of the cholesterol molecules, as inferred with polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). In mixed cholesterol/DPPC monolayers, strong effects from natamycin were only observed when the cholesterol concentration was 50mol% or higher, well above its concentration in a mammalian cell membrane. For a sterol concentration that mimics a real cell membrane in mammals, i.e. with 25mol% of cholesterol, the effects were negligible, which may explain why natamycin has low toxicity when ingested and/or employed to treat superficial fungal infections.
    Colloids and surfaces B: Biointerfaces 10/2014; 122:202–208. DOI:10.1016/j.colsurfb.2014.06.058 · 4.15 Impact Factor
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    ABSTRACT: Aim To evaluate the outcomes of treating deep recalcitrant fungal keratitis with intrastromal voriconazole injection. Methods Twenty-five patients with culture proven fungal keratitis, not responding to a combination of topical 5% natamycin and 1% voriconazole were treated with intrastromal voriconazole (50 µg/0.1 mL) injected in five divided doses around the infiltrate to form a depot of the drug around the circumference of the lesion. Results The mean age of the patients was 52.52±12.21 years and mean time to presentation was 17.12±13.75 days from the onset of symptoms. The mean area of the infiltrate was 30.41±17.2 mm2, hypopyon was present in 88% and all cases had infiltrates that extended beyond the mid-stromal level. Intrastromal voriconazole helped to resolve the infection in 18 (72%) patients and about 15% of these needed more than one injection. Smaller ulcers responded better to treatment. Fusarium spp were responsible for six of the seven cases that failed treatment. Conclusions Targeted delivery of voriconazole by intrastromal injection (50 µg/0.1 mL) is a safe and effective way to treat deep recalcitrant fungal keratitis, though some may need repeated injections. Fusarium keratitis may show suboptimal response but this needs further study.
    British Journal of Ophthalmology 09/2014; 99(2). DOI:10.1136/bjophthalmol-2014-305412 · 2.81 Impact Factor
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