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      Treatment of Severe Acute Bacterial Keratitis in Rabbits Using Continuous Topical Ocular Instillation with Norvancomycin

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          Abstract

          Purpose

          Efficacy of norvancomycin (NVCM) through continuous topical ocular instillation drug delivery (CTOIDD) system for treating severe acute bacterial keratitis infection with Staphylococcus aureus was investigated.

          Methods

          Rabbits with bacterial keratitis were treated using CTOIDD with NVCM (n=13), topical NVCM eye drops (n=11), and CTOIDD with saline (n=8). Clinical signs of keratitis in all groups were assessed consecutively for a week. Bacterial quantification of excised corneas was counted on the fourth and eighth days. Histopathologic examinations were performed to assess inflammatory cell infiltration on the eighth day.

          Results

          All signs of bacterial keratitis were alleviated in CTOIDD with NVCM according to criteria, and the CTOIDD-NVCM group had significantly less inflammation than CTOIDD-saline ( p<0.05), and eye drop-NVCM ( p<0.05). Two eyes in the eye drop-NVCM group, four eyes in the CTOIDD-saline group had corneal perforation (CP), while none of the rabbits showed CP in the CTOIDD-NVCM group. Bacterial counts were significantly less in the CTOIDD with NVCM group in comparison to the eye drop-NVCM ( p<0.05), and CTOIDD-saline ( p<0.05) groups. Severe inflammation and marked inflammatory cell infiltration were found in histopathologic examinations in the CTOIDD-saline and eye drop-NVCM groups, while significantly less inflammation was documented in the CTOIDD-NVCM ( p<0.05) group.

          Conclusion

          CTOIDD with NVCM effectively reduced the severity and treated acute bacterial S. aureus keratitis infection in a rabbit model. The presented approach of CTOIDD with NVCM appears to be a promising therapeutic approach for severe acute bacterial keratitis.

          Most cited references39

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          Antimicrobial Activity of Some Essential Oils—Present Status and Future Perspectives

          Extensive documentation on the antimicrobial properties of essential oils and their constituents has been carried out by several workers. Although the mechanism of action of a few essential oil components has been elucidated in many pioneering works in the past, detailed knowledge of most of the compounds and their mechanism of action is still lacking. This knowledge is particularly important for the determination of the effect of essential oils on different microorganisms, how they work in combination with other antimicrobial compounds, and their interaction with food matrix components. Also, recent studies have demonstrated that nanoparticles (NPs) functionalized with essential oils have significant antimicrobial potential against multidrug- resistant pathogens due to an increase in chemical stability and solubility, decreased rapid evaporation and minimized degradation of active essential oil components. The application of encapsulated essential oils also supports their controlled and sustained release, which enhances their bioavailability and efficacy against multidrug-resistant pathogens. In the recent years, due to increasingly negative consumer perceptions of synthetic preservatives, interest in essential oils and their application in food preservation has been amplified. Moreover, the development of resistance to different antimicrobial agents by bacteria, fungi, viruses, parasites, etc. is a great challenge to the medical field for treating the infections caused by them, and hence, there is a pressing need to look for new and novel antimicrobials. To overcome these problems, nano-encapsulation of essential oils and exploiting the synergies between essential oils, constituents of essential oils, and antibiotics along with essential oils have been recommended as an answer to this problem. However, less is known about the interactions that lead to additive, synergistic, or antagonistic effects. A contributing role of this knowledge could be the design of new and more potent antimicrobial blends, and understanding of the interplay between the components of crude essential oils. This review is written with the purpose of giving an overview of current knowledge about the antimicrobial properties of essential oils and their mechanisms of action, components of essential oils, nano-encapsulated essential oils, and synergistic combinations of essential oils so as to find research areas that can facilitate applications of essential oils to overcome the problem of multidrug-resistant micro-organisms.
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            The Persistent Dilemma of Microbial Keratitis: Global Burden, Diagnosis, and Antimicrobial Resistance

            Microbial keratitis is a potentially blinding condition that must be treated emergently to preserve vision. Although long recognized as a significant cause of corneal blindness, our understanding of its true global scale, associated burden of disease, and etiological patterns remains somewhat limited. Current epidemiological data suggest that microbial keratitis may be epidemic in parts of the world-particularly within South, South-East, and East Asia-and may exceed 2 million cases per year worldwide. Etiological patterns vary between economically developed and developing countries, with bacterial predominance in the former and fungal predominance in the latter. The key to effective management lies in timely diagnosis; however, the current gold standard of stain and culture remains time consuming and often yields no clinically useful results. For this reason, there are attempts to develop highly sensitive and accurate molecular diagnostic tools to provide rapid diagnosis, inform treatment decision making, and minimize the threat of antimicrobial resistance. We provide an overview of these key areas and of avenues for further research toward the goal of more effectively addressing the problem of microbial keratitis on both an individual and public health level.
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              Update on the Management of Infectious Keratitis.

              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 although culture remains the prevailing diagnostic tool, newer techniques such as in vivo confocal microscopy are helpful for diagnosing fungus and Acanthamoeba. 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 associated with keratitis include topical corticosteroids. The large, randomized, controlled Steroids for Corneal Ulcers Trial found that although steroids provided no significant improvement overall, they did seem beneficial for ulcers that were central, deep or large, non-Nocardia, or classically invasive Pseudomonas aeruginosa; for 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 1960s when topical natamycin was introduced. The randomized controlled Mycotic Ulcer Treatment Trial (MUTT) I showed a benefit of topical natamycin over topical voriconazole for fungal ulcers, particularly among those caused by Fusarium. MUTT II showed that oral voriconazole did not improve outcomes overall, although there may have been some effect among Fusarium ulcers. Given an increase in nonserious adverse events, the authors concluded that they could not recommend oral voriconazole. Viral keratitis differs from bacterial and fungal cases in that it is often recurrent and is common in developed countries. The Herpetic Eye Disease Study (HEDS) I showed a significant benefit of topical corticosteroids and oral acyclovir for stromal keratitis. HEDS II showed that oral acyclovir decreased the recurrence of any type of herpes simplex virus keratitis by approximately half. Future strategies to reduce the morbidity associated with infectious keratitis are likely to be multidimensional, with adjuvant therapies aimed at modifying the immune response to infection holding the greatest potential to improve clinical outcomes.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                16 February 2021
                2021
                : 15
                : 617-628
                Affiliations
                [1 ]Department of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University , Changsha, People’s Republic of China
                [2 ]Department of Ophthalmology, Changsha Aier Eye Hospital, Central South University , Changsha, People’s Republic of China
                Author notes
                Correspondence: Ding Lin Department of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University , Changsha, People’s Republic of ChinaTel +86-13787255158 Email linding@csu.edu.cn
                Author information
                http://orcid.org/0000-0002-1195-4841
                http://orcid.org/0000-0003-4225-2778
                Article
                295874
                10.2147/DDDT.S295874
                7896742
                be294f3f-42b2-451d-a617-459c45002b79
                © 2021 Lin et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 05 December 2020
                : 23 January 2021
                Page count
                Figures: 9, Tables: 3, References: 39, Pages: 12
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                severe acute bacterial keratitis,continuous topical instillation,eye drop,norvancomycin,rabbit eyes

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