Pathogenesis of microbial keratitis

Fungal keratitis is a severe corneal infection that often results in blindness and eye loss. The disease is most prevalent in tropical and subtropical climates, and infected individuals are frequently young agricultural workers of low socioeconomic status. Early diagnosis and treatment can preserve vision. Here, we discuss the fungal keratitis diagnostic literature and estimate the global burden through a complete systematic literature review from January, 1946 to July, 2019. An adapted GRADE score was used to evaluate incidence papers-116 studies provided the incidence of fungal keratitis as a proportion of microbial keratitis and 18 provided the incidence in a defined population. We calculated a minimum annual incidence estimate of 1 051 787 cases (736 251-1 367 323), with the highest rates in Asia and Africa. If all culture-negative cases are assumed to be fungal, the annual incidence would be 1 480 916 cases (1 036 641-1 925 191). In three case series, 8-11% of patients had to have the eye removed, which represents an annual loss of 84 143-115 697 eyes. As fungal keratitis probably affects over a million people annually, an inexpensive, simple diagnostic method and affordable treatment are needed in every country.

The global incidence and diagnosis of fungal keratitis.

Background Fungal keratitis (FK) is a serious pathogenic condition usually associated with significant ocular morbidity. Natamycin (NAT) is the first-line and only medication approved by the Food and Drug Administration for the treatment of FK. However, NAT suffers from poor corneal penetration, which limits its efficacy for treating deep keratitis. Purpose The objective of this work was to prepare NAT solid lipid nanoparticles (NAT-SLNs) to achieve sustained drug release and increased corneal penetration. Methods NAT-SLNs were prepared using the emulsification-ultrasonication technique. Box- Behnken experimental design was applied to optimize the effects of independent processing variables (lipid concentration [X1], surfactant concentration [X2], and sonication frequency [X3]) on particle size (R1), zeta potential (ZP; R2), and drug entrapment efficiency (EE%) (R3) as responses. Drug release profile, ex vivo corneal permeation, antifungal susceptibility, and cytotoxicity of the optimized formula were evaluated. Results The optimized formula had a mean particle size of 42 r.nm (radius in nanometers), ZP of 26 mV, and EE% reached ~85%. NAT-SLNs showed an extended drug release profile of 10 hours, with enhanced corneal permeation in which the apparent permeability coefficient (Papp) and steady-state flux (Jss) reached 11.59×10-2 cm h-1 and 3.94 mol h-1, respectively, in comparison with 7.28×10-2 cm h-1 and 2.48 mol h-1 for the unformulated drug, respectively. Antifungal activity was significantly improved, as indicated by increases in the inhibition zone of 8 and 6 mm against Aspergillus fumigatus ATCC 1022 and a Candida albicans clinical isolate, respectively, and minimum inhibitory concentration values that were decreased 2.5-times against both of these pathogenic strains. NAT-SLNs were found to be non-irritating to corneal tissue. NAT-SLNs had a prolonged drug release rate, that improved corneal penetration, and increased antifungal activity without cytotoxic effects on corneal tissues. Conclusion Thus, NAT-SLNs represent a promising ocular delivery system for treatment of deep corneal keratitis.

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Natamycin solid lipid nanoparticles - sustained ocular delivery system of higher corneal penetration against deep fungal keratitis: preparation and optimization.

BACKGROUND Fungal keratitis is basically treated by medications. Several cases of fungal keratitis were reported around the world to have been treated successfully by corneal graft--penetrating keratoplasty (PKP). Studies have shown that PKP is a useful treatment, preserves eye globe integrity, and rehabilitates vision in patients with advanced fungal keratitis. AIM To study the use of penetrating keratoplasty for the treatment of severe fungal keratitis that could not be cured by antifungal medication. METHODS The authors conducted a retrospective analysis of all cases (five cases) of severe fungal keratitis treated and followed-up at the Department of Ophthalmology, Soroka University Medical Center during 2007 and 2008, in which therapeutic PKP was performed. There were one male and 4 females. The age range was between 27 and 78 years. The follow-up period ranged from 4 to 15 months. RESULTS Corneal graft remained clear during follow-up in most patients. There was no recurrence of fungal infection and the visual acuity ranged from counting fingers (FC) from 50 cm to 6/36. Complications in some patients included graft rejection in one patient with re-graft which remained clear during follow-up period of 6 months, another patient had a minimal partial graft rejection and incipient cataract which didn't necessitate further intervention. DISCUSSION AND CONCLUSIONS PKP is an effective treatment for fungal keratitis that does not respond to antifungal medication. Early surgical intervention before deterioration is recommended.

Treatment of fungal keratitis by penetrating keratoplasty

Pimaricin (natamycin) is a small polyene macrolide antibiotic used worldwide. This efficient antimycotic and antiprotozoal agent, produced by several soil bacterial species of the genus Streptomyces, has found application in human therapy, in the food and beverage industries and as pesticide. It displays a broad spectrum of activity, targeting ergosterol but bearing a particular mode of action different to other polyene macrolides. The biosynthesis of this only antifungal agent with a GRAS status has been thoroughly studied, which has permitted the manipulation of producers to engineer the biosynthetic gene clusters in order to generate several analogues. Regulation of its production has been largely unveiled, constituting a model for other polyenes and setting the leads for optimizing the production of these valuable compounds. This review describes and discusses the molecular genetics, uses, mode of action, analogue generation, regulation and strategies for increasing pimaricin production yields.

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Biotechnological production and application of the antibiotic pimaricin: biosynthesis and its regulation

Fungal keratitis remains a challenging and often elusive diagnosis in geographic regions where it is endemic. Marred by delays in diagnosis, the sequelae of corneal fungal infections, though preventable, can be irreversible. Recent studies and advances in the arena have broadened the approach and treatment to mycotic keratitis. This review will discuss current diagnostic modalities of fungal keratitis and will particularly focus on treatment regimens. It will also explore future therapeutic models and critique the potential benefit of each.

Zubair Ansari

Papers

Current Thoughts in Fungal Keratitis: Diagnosis and Treatment