Bacterial keratitis: identifying the areas of clinical uncertainty

Tuft, Stephen; Somerville, Tobi; Li, Ji-Peng Olivia; Neal, Timothy; De, Surya K.; Horsburgh, Malcolm J.; Fothergill, Joanne L.; Foulkes, Daniel M.; Kaye, Stephen B.

doi:10.1016/j.preteyeres.2021.101031

Cited by 46 publications

(74 citation statements)

References 409 publications

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“…[34][35][36][37] PK: ocular penetration of FQs For a topically applied antimicrobial, the PK refers to the process by which it reaches its target site and determines the optimum dosage regimen (how much and how often) to maintain the concentration in the cornea within the therapeutic range. 3 Important components include the half-life, protein binding, and the time that the concentration of the antimicrobial in the cornea remains above the MIC. Common associations with corneal ulceration, such as reflex lacrimation, inflammatory discharge, nasolacrimal duct obstruction or a keratinised ocular surface, can all affect the PK.…”

Section: Open Accessmentioning

confidence: 99%

“…40 Due to limited data to establish ophthalmic breakpoints, EUCAST recommends epidemiological cut-off values as an alternative to indicate susceptibility to topical agents, determined from a comparison of the antimicrobial MIC distribution representative of the wild-type bacterial population with the MIC distribution in a population with a well characterised resistance mechanism to the antibiotic. 3 Until topical ophthalmic breakpoints are established, we believe that it is preferable for the microbiology laboratory to provide the clinician with both the MIC and the bacterial susceptibility estimated from the systemic breakpoint. The clinician could then refer to the expected corneal concentration, for example, the first quartile in online supplemental table 1, and decide if the MIC is above or below that concentration.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

“…For example, if the MIC is close to the achievable concentration of the antimicrobial in the cornea the options would be to increase the dosage (eg, frequency of Open access better clinical outcome even though it has a higher MIC. 3 The MICs of FQs to the bacteria commonly isolated from bacterial keratitis are presented in table 1.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

“…It is a significant cause of preventable corneal blindness worldwide, with an estimated incidence range in high-income countries of 4.5–37.7 cases per 100 000 population-year 1. A population-based study in China estimated the prevalence of past or active infectious keratitis to be 192 (95% CI 171 to 213) per 100 000, with a prevalence of presumed viral keratitis of 110, bacterial keratitis 75 and fungal keratitis 7 per 100 000 2 3. The relative proportion of cases due to fungal infection is higher in equatorial regions 4.…”

Section: Introductionmentioning

confidence: 99%

“…The MIC is the lowest concentration (mg/L) of an antimicrobial that will inhibit the visible growth of the bacterium, and the MIC 90 the concentration at which≥90% growth is inhibited, within strictly controlled conditions of incubation time and temperature 3 32 33. The MIC, and other antimicrobial parameters such as dosage, PK and PD, and therapeutic success (clinical outcome), are used by regional regulatory bodies such as the European Committee on Antimicrobial Susceptibility Testing (EUCAST) or the Clinical & Laboratory Standards Institute (USA guidelines) to establish a threshold (breakpoint) concentration that determines whether the isolated bacteria is susceptible or resistant 3. The breakpoint is a chosen concentration (mg/L) of the antimicrobial that defines whether there is a high likelihood of clinical success for that agent against the isolated bacterium.…”

Section: Introductionmentioning

confidence: 99%

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Potential new fluoroquinolone treatments for suspected bacterial keratitis

et al. 2022

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Topical fluoroquinolones (FQs) are an established treatment for suspected microbial keratitis. An increased FQ resistance in some classes of bacterial pathogens is a concern. Some recently developed FQs have an extended spectrum of activity, making them a suitable alternative for topical ophthalmic use. For example, the new generation FQs, avarofloxacin, delafloxacin, finafloxacin, lascufloxacin, nadifloxacin, levonadifloxacin, nemonoxacin and zabofloxacin have good activity against the common ophthalmic pathogens such asStaphylococcus aureus,Pseudomonas aeruginosa,Streptococcus pneumoniaeand several of theEnterobacteriaceae. However, because there are no published ophthalmic break-point concentrations, the susceptibility of an isolated micro-organism to a topical FQ is extrapolated from systemic break-point data and wild type susceptibility. The purpose of this review is to compare the pharmacokinetics and pharmacodynamics of the FQs licensed for topical ophthalmic use with the same parameters for new generation FQs. We performed a literature review of the FQs approved for topical treatment and the new generation FQs licensed to treat systemic infections. We then compared the minimum inhibitory concentrations (MIC) of bacterial isolates and the published concentrations that FQs achieved in the cornea and aqueous. We also considered the potential suitability of new generation FQs for topical use based on their medicinal properties. Notably, we found significant variation in the reported corneal and aqueous FQ concentrations so that reliance on the reported mean concentration may not be appropriate, and the first quartile concentration may be more clinically relevant. The provision of the MIC for the microorganism together with the achieved lower (first) quartile concentration of a FQ in the cornea could inform management decisions such as whether to continue with the prescribed antimicrobial, increase the frequency of application, use a combination of antimicrobials or change treatment.

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Section: Open Accessmentioning

confidence: 99%

Section: Pharmacodynamicsmentioning

confidence: 99%

Section: Pharmacodynamicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potential new fluoroquinolone treatments for suspected bacterial keratitis

et al. 2022

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Rapid Point-of-Care Identification of Aspergillus Species in Microbial Keratitis

Gunasekaran,

Chandrasekaran,

Rajarathinam

et al. 2023

JAMA Ophthalmol

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ImportanceMicrobial keratitis (MK) is a common cause of unilateral visual impairment, blindness, and eye loss in low-income and middle-income countries. There is an urgent need to develop and implement rapid and simple point-of-care diagnostics for MK to increase the likelihood of good outcomes.ObjectiveTo evaluate the diagnostic performance of the Aspergillus-specific lateral-flow device (AspLFD) to identify Aspergillus species causing MK in corneal scrape and corneal swab samples of patients presenting with microbial keratitis.Design, Setting, and ParticipantsThis diagnostic study was conducted between May 2022 and January 2023 at the corneal clinic of Aravind Eye Hospital in Madurai, Tamil Nadu, India. All study participants were recruited during their first presentation to the clinic. Patients aged 15 years or older met the eligibility criteria if they were attending their first appointment, had a corneal ulcer that was suggestive of a bacterial or fungal infection, and were about to undergo diagnostic scrape and culture.Main Outcomes and MeasuresSensitivity and specificity of the AspLFD with corneal samples collected from patients with MK. During routine diagnostic scraping, a minimally invasive corneal swab and an additional corneal scrape were collected and transferred to aliquots of sample buffer and analyzed by lateral-flow device (LFD) if the patient met the inclusion criteria. Photographs of devices were taken with a smartphone and analyzed using a ratiometric approach, which was developed for this study. The AspLFD results were compared with culture reports.ResultsThe 198 participants who met the inclusion criteria had a mean (range) age of 51 (15-85) years and included 126 males (63.6%). Overall, 35 of 198 participants with corneal scrape (17.7%) and 17 of 40 participants with swab samples (42.5%) had positive culture results for Aspergillus species. Ratiometric analysis results for the scrape samples found that the AspLFD achieved high sensitivity (0.89; 95% CI, 0.74-0.95), high negative predictive value (0.97; 95% CI, 0.94-0.99), low negative likelihood ratio (0.12; 95% CI, 0.05-0.30), and an accuracy of 0.94 (95% CI, 0.90-0.97). Ratiometric analysis results for the swab samples showed that the AspLFD had high sensitivity (0.94; 95% CI, 0.73-1.00), high negative predictive value (0.95; 95% CI, 0.76-1.00), low negative likelihood ratio (0.07; 95% CI, 0.01-0.48), and an accuracy of 0.88 (95% CI, 0.73-0.96).Conclusions and RelevanceResults of this diagnostic study suggest that AspLFD along with the ratiometric analysis of LFDs developed for this study has high diagnostic accuracy in identifying Aspergillus species from corneal scrapes and swabs. This technology is an important step toward the provision of point-of-care diagnostics for MK and could inform the clinical management strategy.

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Photothermal Iron‐Based Riboflavin Microneedles for the Treatment of Bacterial Keratitis via Ion Therapy and Immunomodulation

Zhou,

Zhang,

Wei

et al. 2024

Adv Healthcare Materials

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Bacterial biofilm formation protects bacteria from antibiotics and the immune system, excessive inflammation further complicates treatment. Here, iron‐based metal–organic framework (MIL‐101)‐loaded riboflavin nanoparticles are designed for the therapeutic challenge of biofilm infection and hyperinflammation in bacterial keratitis. Specifically, MIL‐101 produces a thermal effect under exogenous near‐infrared light irradiation, which synergizes with ferroptosis‐like bacterial death induced by iron ions to exert an effective biofilm infection eradication effect. On the other hand, the disintegration of MIL‐101 sustains the release of riboflavin, which inhibits the pro‐inflammatory response of macrophage over‐activation by modulating their phenotypic switch. In addition, to solve the problems of short residence time, poor permeability, and low bioavailability of corneal medication, the MR@MN microneedle patch is further prepared by loading nanoparticles into SilMA hydrogel, which ultimately achieves painless, transepithelial, and highly efficient drug delivery. In vivo and ex vivo experiments demonstrate the effectiveness of this approach in eliminating bacterial infection and promoting corneal healing. Therefore, the MRMN patch, acting as an ocular drug delivery system with the ability of rapid corneal healing, promises a cost‐effective solution for the treatment of bacterial keratitis, which may also lead to a new approach for treating bacterial keratitis in clinics.

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Bacterial keratitis: identifying the areas of clinical uncertainty

Cited by 46 publications

References 409 publications

Potential new fluoroquinolone treatments for suspected bacterial keratitis

Potential new fluoroquinolone treatments for suspected bacterial keratitis

Rapid Point-of-Care Identification of Aspergillus Species in Microbial Keratitis

Photothermal Iron‐Based Riboflavin Microneedles for the Treatment of Bacterial Keratitis via Ion Therapy and Immunomodulation

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