Multifunctional Polymer Vesicles for Synergistic Antibiotic-Antioxidant Treatment of Bacterial Keratitis.

As an acute ophthalmic infection, bacterial keratitis (BK) can lead to severe visual morbidity, such as corneal perforation, intraocular infection, and permanent corneal opacity, if rapid and effective treatments are not available. In addition to eradicating pathogenic bacteria, protecting corneal tissue from oxidative damage and promoting wound healing by relieving inflammation are equally critical for the efficient treatment of BK. Besides, it is very necessary to improve the bioavailability of drugs by enhancing the ocular surface adhesion and corneal permeability. In this investigation, therefore, a synergistic antibiotic-antioxidant treatment of BK was achieved based on multifunctional block copolymer vesicles, within which ciprofloxacin (CIP) was simultaneously encapsulated during the self-assembly. Due to the phenylboronic acid residues in the corona layer, these vesicles exhibited enhanced muco-adhesion, deep corneal epithelial penetration, and bacteria-targeting, which facilitated the drug delivery to corneal bacterial infection sites. Additionally, the abundant thioether moieties in the hydrophobic membrane enabled the vesicles to both have ROS-scavenging capacity and accelerated CIP release at the inflammatory corneal tissue. In vivo experiments on a mice model demonstrated that the multifunctional polymer vesicles achieved efficient treatment of BK, owing to the enhanced corneal adhesion and penetration, bacteria targeting, ROS-triggered CIP release, and the combined antioxidant-antibiotic therapy. This synergistic strategy holds great potential in the treatment of BK and other diseases associated with bacterial infections.

Intravitreal triple therapy with vancomycin, ceftazidime, and moxifloxacin for bacterial endophthalmitis: A Twelve-year experience.

PURPOSE: Increasing rates of antibiotic resistance in endophthalmitis have been reported. This study examines outcomes of triple therapy with intravitreal vancomycin, ceftazidime, and moxifloxacin for endophthalmitis. METHODS: Retrospective, consecutive series of all patients treated with abovementioned intravitreal antibiotics from January 2009 to June 2021. Percentages of eyes attaining greater than or equal to 20/200 and 20/50 Snellen visual acuities and adverse events were evaluated. RESULTS: 112 eyes met inclusion criteria. 63 of 112 eyes (56%) achieved a visual acuity of 20/200 during follow-up, with 39 (35%) returning to at least 20/50. In subgroup analysis, 23 of 24 (96%) eyes with post-cataract endophthalmitis obtained ≥ 20/200 acuity and 21 of 24 (88%) obtained ≥ 20/50 acuity during follow-up. There were no cases of macular infarction. CONCLUSIONS: Intravitreal moxifloxacin (160 µg/0.1 mL) was well tolerated as an adjunct to vancomycin and ceftazidime for bacterial endophthalmitis. Use of this novel combination offers several theoretical advantages compared to standard therapy with two antibiotics, including expanded gram-negative coverage and potential synergy, and may be particularly valuable in geographies where the local antibiogram supports empiric use. Further study is merited to verify the safety and efficacy profile.

Susceptibility pattern of bacterial isolates in equine ulcerative keratitis: Implications for empirical treatment at a university teaching hospital in Sydney.

Corneal ulceration is a common ophthalmic condition in horses. It is frequently caused by trauma to the corneal surface, followed by secondary infection by commensal or pathogenic organisms including Streptococcus equi subspecies zooepidemicus, Pseudomonas aeruginosa and Staphylococcus spp. Emerging antimicrobial resistance amongst these organisms has raised the need for appropriate antimicrobial therapy selection, to optimise treatment efficacy while minimising further antimicrobial resistance. Medical records of 38 horses presented at the University Veterinary Teaching Hospital Camden for ulcerative keratitis between 2010 and 2020 were reviewed to identify those with positive bacterial cultures and antimicrobial susceptibility profiles (13/38). Common susceptibility patterns were identified and used to guide the empirical treatment of equine bacterial corneal ulcers. Pseudomonas spp. (64.3%), Streptococcus equi subspecies zooepidemicus (14.3%) and Actinobacillus spp. (14.3%) were most commonly identified. Susceptibility to amikacin, gentamicin and ciprofloxacin was observed in 100%, 66.7% and 85.7% Pseudomonas spp. isolates respectively. Resistance to polymyxin B and neomycin occurred in 85.7% and 71.4% of Pseudomonas spp., respectively. All Streptococcus equi subspecies zooepidemicus organisms in this study were susceptible to ceftiofur, cephalexin, penicillin and ampicillin, while they were all resistant to gentamicin, neomycin, enrofloxacin and marbofloxacin. Predominating in this study, Pseudomonas spp. maintained overall aminoglycoside susceptibility despite some emerging resistance, and good fluoroquinolone susceptibility. High resistance to Polymyxin B could have arisen from its common use as first-line therapy for bacterial corneal ulcers. Although further research is required, these new findings about predominant bacteria in equine corneal ulceration in the Camden region and their antimicrobial susceptibility patterns can be used to guide the empirical treatment of bacterial corneal ulcers in horses.

A Literature-Based Review and Analysis of the Pharmacodynamics of the Dose Frequency of Topical 0.3% Ciprofloxacin and 0.3% Ofloxacin in the Day-1 Treatment of Bacterial Keratitis.

Purpose: To determine the appropriate dose frequency for the second-generation fluoroquinolones (2FQs), ciprofloxacin 0.3% and ofloxacin 0.3%, in the day-1 treatment of bacterial keratitis (BK) based on the corneal concentrations achievable and required Minimum Inhibitory Concentration90 (MIC90) of common BK isolates. Methods: Literature-based ocular MIC90 required to treat bacterial isolates of BK patients were determined for each fluoroquinolone. Published corneal concentrations for each 2FQ, and the drop regimens used to reach these concentrations, were then analyzed to determine the relationship between the corneal 2FQ concentration and the amount of drug applied per hour and the total amount applied. Results: Significant relationships were found to exist for corneal concentrations of both ciprofloxacin and ofloxacin and the amount of drug applied per hour (both P = 0.005), and the total amount of drug applied (P = 0.003 and P = 0.0004, respectively). Derived ciprofloxacin drops/hour corneal concentrations agreed well with both a literature-based regimen and the manufacturers' day-1 drop regimen for various MIC90. Derived ofloxacin drops per hour indicated a higher rate than that suggested by the manufacturer. Conclusions: Both a literature-based and the manufacturers' drop regimens for the day-1 treatment of BK using 0.3% ciprofloxacin have a pharmacodynamic basis, which is related to the required MIC90 of commonly encountered isolates in BK. Dose frequency for 0.3% ofloxacin should be in line with the manufacturers' maximum suggested drop regimen. Commonly suggested drop regimens below these recommendations for either FQ may need to be revised in view of these findings.

The clinical treatment of bacterial keratitis: A review of drop instillation regimes.

Bacterial keratitis (BK) presentations are often treated using the commercially available second-generation fluoroquinolones ciprofloxacin 0.3% and ofloxacin 0.3% as monotherapy. The guidelines available for instillation regimes are often not supported by data from clinical studies. This review examines the peer-reviewed clinical studies and compared treatment failure rates for ciprofloxacin 0.3% and ofloxacin 0.3% for BK in relation to Day-1 drop-regimes. From the statistical analysis, this review derived evidence-based clinically applicable minimum drop-regimes for the treatment of BK on Day-1. Lower numbers of drops of ciprofloxacin on Day-1 were significantly associated with increased treatment failure rates (p < 0.002). The derived minimum number of drops on Day for ciprofloxacin on Day-1 was 47 drops, and for ofloxacin 24 drops. The mean number of drops used in the clinical studies was significantly lower than the manufacturers' recommended Day-1 regimes for both ciprofloxacin (p = 0.0006) and ofloxacin (p = 0.048). From Day-3 to -6 of treatment the drop rates for ciprofloxacin relative to recommended rates were higher, and for ofloxacin lower (p = 0.014). The findings of this review were then compared with a representative sample of published guidelines and case studies to determine the validity of applying those drop-regimes in clinical practice. Although the manufacturers' suggested minimum drop-regimes on Day-1 were significantly different (120 drops ciprofloxacin, 34 drops ofloxacin, p < 0.0001), many of the published guidelines suggested the same drop-regime for both fluoroquinolones. The suggested drop numbers on Day-1 for ciprofloxacin in these guidelines and case studies were significantly less than those used in the clinical studies (p = 0.043). Increased treatment failure rates for ciprofloxacin are associated with lower drop numbers on Day-1. The Day-1 dosing rates for ciprofloxacin and ofloxacin should be considered separately, and the regimes suggested in published guidelines and case studies may need be re-considered in light of the findings of this review.

PACK Cross-Linking as Adjuvant Therapy Improves Clinical Outcomes in Culture-Confirmed Bacterial Keratitis.

PURPOSE: We recently showed the positive clinical effects of combining accelerated corneal cross-linking (PACK-CXL) with antibiotic treatment in patients with presumed bacterial keratitis. In this study, we compare the impacts of a combined PACK-CXL/standard antibiotic treatment (PACK-ABX group) with standard antibiotic treatment alone (ABX group) in patients with culture-confirmed bacterial keratitis. METHODS: We reviewed patients with moderate and severe bacterial keratitis and confirmed bacterial cultures. Clinical outcomes were compared for standard antibiotic treatment alone, before the initiation of PACK-CXL, and after adjuvant use of PACK-CXL. RESULTS: A total of 47 eyes of 47 patients were included: 26 eyes in the PACK-ABX group and 21 eyes in the ABX group. Pathogens, baseline demographics (besides age), and clinical parameters were similar between the 2 groups. The PACK-ABX patients had better final uncorrected visual acuity [mean difference 0.57 Logarithm of the Minimum Angle of Resolution, 95% Confidence Interval (CI): 0.16-0.99, P = 0.07] and best-corrected visual acuity (mean difference 0.70 Logarithm of the Minimum Angle of Resolution, 95% CI: 0.23-1.16, P = 0.04), shorter reepithelialization time (mean difference 9.63 days, 95% CI: 3.14-16.12, P = 0.004), and reduced number of clinic visits (mean difference 4.8 meetings, 95% CI: 1.4-8.2, P = 0.007) and need for tectonic grafts (0 vs. 33.3%, P = 0.002). A multivariate analysis controlling for age, sex, ulcer size, and Gram stain showed that PACK-ABX treatment remained significantly associated with reepithelialization time (ß = 14.5, P = 0.001). CONCLUSIONS: In our study, PACK-CXLs addition to the standard of care in cases of culture-proven bacterial keratitis had a positive effect on the final visual acuity and time to resolution, compared with the standard-of-care treatment.

Ozonoterapia como tratamiento coadyuvante en la úlcera corneal grave bacteriana / Ozone therapy as adjunctive treatment in severe bacterial corneal ulcer / Ozonoterapia como tratamento adjuvante em úlcera bacteriana da córnea grave

Introducción: La evolución espontánea o los casos mal tratados de la úlcera corneal conllevan el riesgo de extensión de la infección, con severa afectación visual e integridad estructural del ojo. Objetivo: Describir las características clínico-epidemiológicas de pacientes con úlcera corneal grave bacteriana tratada con ozonoterapia local coadyuvante al tratamiento protocolizado. Método: Se realizó un estudio observacional, descriptivo y transversal con 48 pacientes ingresados en el servicio de Oftalmología del Hospital General Docente "Dr. Juan Bruno Zayas Alfonso", de Santiago de Cuba, en el periodo de enero de 2017 a diciembre de 2019. Las variables del estudio fueron: edad, sexo, factores predisponentes, microorganismos, signos de mejoría clínica, resultados al tratamiento y complicaciones. Para la validación estadística se utilizó prueba Chi-cuadrado. Resultados: La edad promedio de los pacientes fue de 54,1 años, el 62,5 % eran hombres. Predominó el trauma ocular (63,3 %) en el sexo masculino y enfermedades oculares (44,4 %) en el femenino. La mejoría de los signos fue más representativa a los 14 días. Se logró resultados satisfactorios en el 100 % de los pacientes con microorganismos grampositivos. El 10,4 % presentó perforación corneal. Conclusiones: La ozonoterapia es una terapia válida como tratamiento en la úlcera corneal grave de etiología bacteriana y responde a la búsqueda de alternativas para pacientes con resistencia a los tratamientos antibacterianos que se ofertan en el cuadro básico de salud.

ABSTRACT Introduction: Spontaneous evolution or poorly treated cases of corneal ulcer carry the risk of extension of the infection, with severe visual impairment and damage to the structural integrity of the eye. Objective: To describe the clinical-epidemiological characteristics of patients with severe bacterial corneal ulcer treated with local ozone therapy as an adjunct to the standard protocol treatment. Method: An observational, descriptive and cross-sectional study was carried out on 48 patients admitted to the Ophthalmology service of the Hospital General Docente "Dr. Juan Bruno Zayas Alfonso", from Santiago de Cuba, in the period from January 2017 to December 2019. The study variables were: age, gender, predisposing factors, microorganisms, signs of clinical improvement, treatment results and complications. Chi-square test was used for statistical validation. Results: The average age of the patients was 54.1 years; 62.5% of them were men. Ocular trauma (63.3%) predominated in males, and ocular diseases (44.4%) in females. The improvement of the signs was more common after 14 days. Satisfactory results were achieved in 100% of patients with gram-positive organisms. 10.4% presented corneal perforation. Conclusions: Ozone therapy is valid as a treatment for severe corneal ulcer of bacterial etiology, and responds to the search for alternatives for patients with resistance to the antibacterial treatments that are offered in the basic health system.

RESUMO Introdução: A evolução espontânea ou casos mal tratados de úlcera de córnea trazem o risco de extensão da infecção, com comprometimento visual grave e integridade estrutural do olho. Objetivo: Descrever as características clínico-epidemiológicas de pacientes com úlcera bacteriana de córnea grave tratados com ozonioterapia local como coadjuvante ao tratamento protocolizado. Método: Foi realizado um estudo observacional, descritivo e transversal com 48 pacientes internados no serviço de Oftalmologia do Hospital General Docente "Dr. Juan Bruno Zayas Alfonso", de Santiago de Cuba, no período de janeiro de 2017 a dezembro de 2019. As variáveis do estudo foram: idade, sexo, fatores predisponentes, microrganismos, sinais de melhora clínica, resultados do tratamento e complicações. O teste do qui-quadrado foi usado para validação estatística. Resultados: A idade média dos pacientes foi de 54,1 anos, 62,5% eram homens. O trauma ocular (63,3%) predominou no sexo masculino e as doenças oculares (44,4%) no feminino. A melhoria da sinalização foi mais representativa aos 14 dias. Resultados satisfatórios foram alcançados em 100% dos pacientes com organismos gram-positivos. 10,4% apresentaram perfuração corneana. Conclusões: A ozonioterapia é uma terapia válida como tratamento para úlcera de córnea grave de etiologia bacteriana e responde à busca de alternativas para pacientes com resistência aos tratamentos antibacterianos que são oferecidos no quadro básico de saúde.

Comparison of Clinical Features and Treatment Outcomes of Pseudomonas aeruginosa Keratitis in Contact Lens and Non-Contact Lens Wearers.

PURPOSE: To compare the outcomes of Pseudomonas aeruginosa keratitis (PAK) in contact lens wearers (CLWs) and non-contact lens wearers (non-CLWs) and identify risk factors for poor visual acuity (VA) outcomes in each group. DESIGN: Retrospective cohort study METHODS: Two hundred fourteen consecutive cases of PAK were included between January 2006 and December 2019. Clinical features, microbiologic results, and treatment course were compared between CLW and non-CLW groups. Analyses of clinical features predicting poor final VA were performed. RESULTS: This study identified 214 infected eyes in 207 patients with PAK, including 163 eyes (76.2%) in CLWs and 51 eyes (23.8%) in non-CLWs. The average age was 39.2 years in CLWs and 71.9 years in non-CLWs (P < .0001). The average logMAR visual acuity (VA) at presentation was 1.39 in CLWs and 2.17 in non-CLWs (P < .0001); average final VA was 0.76 in CLWs and 1.82 in non-CLWs (P < .0001). Stromal necrosis required a procedural or surgical intervention in 13.5% of CLWs and 49.0% of non-CLWs (P < .0001). A machine learning-based analysis yielded a list of clinical features that most strongly predict a poor VA outcome (worse than 20/40), including worse initial VA, older age, larger size of infiltrate or epithelial defect at presentation, and greater maximal depth of stromal necrosis. CONCLUSIONS: Non-CLWs have significantly worse VA outcomes and required a higher rate of surgical intervention, compared with CLWs. Our study elucidates risk factors for poor visual outcomes in non-CLWs with PAK.

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

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.

Endophthalmitis Prophylaxis Failures in Patients Injected With Intracameral Antibiotic During Cataract Surgery.

PURPOSE: To estimate the association of cefuroxime and moxifloxacin in relation to the occurrence of endophthalmitis following phacoemulsification cataract surgery. DESIGN: Retrospective clinical cohort study. METHODS: We studied patients with noncomplex phacoemulsification cataract surgery in Kaiser Permanente Northern California during 2014-2019. Data were obtained for acute, postoperative endophthalmitis within 90 days of phacoemulsification, including culture and antibiogram results, intracameral and topical antibiotic agent, and dose. In a post hoc analysis, we also examined preoperative anterior chamber depth (ACD) and postoperative anterior chamber volume (ACV). RESULTS: Of 216,141 surgeries, endophthalmitis occurred in 0.020% of moxifloxacin-injected eyes and 0.013% of cefuroxime eyes (relative risk 1.62 with 95% CI 0.82-3.20, P = .16). Of the 34 (0.016%) cases of endophthalmitis, cefuroxime 1 mg was injected into 13 eyes and moxifloxacin 0.1% into 21 eyes. Organisms with antibiograms were identified in 12 (35%) cases. Of these, bacteria recovered from cefuroxime-injected eyes were resistant to cefuroxime in all cases (4/4), with Enterococcus comprising half of these. In eyes injected with moxifloxacin 0.1%, 6 out of 7 organisms were sensitive to moxifloxacin injected with 0.1 mL and in 1 eye injected with 1 mL. Streptococcus was the most common organism recovered (6/9) in moxifloxacin-injected eyes. Preoperative ACD and postoperative calculated ACV were higher in eyes injected with moxifloxacin. CONCLUSIONS: Endophthalmitis cases with positive cultures were generally related to organism resistance in cefuroxime eyes but to sensitive organisms in moxifloxacin eyes. Moxifloxacin doses may have been insufficient in eyes with larger ACV.

Proteus mirabilis Keratitis: Risk Factors, Clinical Features, Treatment Outcomes, and Microbiological Characteristics.

PURPOSE: To characterize the risk factors, clinical presentations, management choices, and outcomes of Proteus mirabilis keratitis. METHODS: In this retrospective study, 26 culture-proven cases of P. mirabilis infections were diagnosed and treated between 1998 and 2019 at the University of Pittsburgh Medical Center. Medical records were available for 14 keratitis cases and were reviewed for demographic information, ocular risk factors, and treatment outcomes. RESULTS: Sixteen eyes of 14 patients were included in the study. The average age was 47.8 ± 19.3 years, with a median follow-up time of 6 months. The most common ocular risk factors were poor ocular surface and contact lens use in 57.1% and 42.9% of cases, respectively. Eleven of the 14 patients (78.6%) had positive corneal cultures, and 13 of the 14 patients (92.9%) had positive conjunctiva or eyelid cultures. All isolates were susceptible to ciprofloxacin, ofloxacin, moxifloxacin, gatifloxacin, and cefazolin. Surgical intervention was required in 4 patients (28.6%). Average LogMAR visual acuity was 1.3 ± 1.0 at presentation and 0.9 6 ± 1.0 at the most recent follow-up visit. CONCLUSIONS: Proteus mirabilis is an uncommon cause of microbial keratitis. Patients with poor ocular surface and those who use contact lens are at increased risk for developing this cause of keratitis. Empiric treatment with fortified antibiotics or fluoroquinolones seemed to provide effective coverage for P. mirabilis.

Treatment of Severe Infectious Keratitis With Scleral Contact Lenses as a Reservoir of Moxifloxacin 0.5.

PURPOSE: To report the outcomes of using scleral contact lenses as antibiotic reservoirs as a therapeutic approach in a case series of severe infectious keratitis and to discuss the clinical potential. METHODS: This was a prospective consecutive case series study of 12 eyes treated for infectious keratitis at the "Conde de Valenciana" Institute of Ophthalmology. A scleral lens (SL) filled with 0.5% moxifloxacin was used as a reservoir and replaced every 24 hours until epithelization was complete or the culture report and/or antibiogram demonstrated either a microorganism not susceptible to or resistant to moxifloxacin. RESULTS: The study included 12 eyes of 12 patients (7 women; 58.33%; average age of 63 ± 20.11 years). All patients completed at least 1 month of follow-up. Patients had a diagnosis of infectious keratitis, and the SL was fitted on initial consultation. Of the 12 eyes, 7 had culture-positive bacterial infection, 2 eyes were mycotic, and 3 eyes had no culture growth. In 3 eyes, SL was discontinued because of the lack of response (one eye) and to the presence of mycotic infection (2 eyes). All infections resolved favorably at the final follow-up. CONCLUSIONS: The use of SLs could be an alternative for antibiotic impregnation and treatment of infectious keratitis. No complications or side effects were observed related to the use of the scleral contact lens as a reservoir for the antibiotic. This treatment modality could offer a comfortable treatment for the patient, ensuring good impregnation and maintenance of antibiotic concentrations during the 24-hour wear periods.

Acute syphilitic posterior placoid chorioretinopathy presenting as atypical multiple evanescent white dot syndrome.

BACKGROUND: This paper reports the case of a young man who presented with syphilis masquerading as multiple evanescent white dots syndrome (MEWDS), which turned out to be an acute syphilitic posterior placoid chorioretinopathy (ASPPC) during follow-up. CASE PRESENTATION: A 59-year-old healthy male consulted for a three days' history of visual impairment in both eyes. On multimodal imaging, he was diagnosed as MEWDS. Fundus fluorescein angiography (FFA) showed early peripheral bilateral granular hyperfluorescence that correlated with the yellow-white dots found on fundus exam. Indocyanine green angiography (ICGA) depicted hypofluorescent dots on late phase. Spectral-domain optical coherence tomography (SD-OCT) revealed numerous inner retinal highly reflective deposits in the outer nuclear layer and disruption of the ellipsoid zone. After initial improvement, he presented again for a sudden visual loss at 3 weeks. FFA, ICGA and SD-OCT demonstrated the same but more numerous and outer lesions suggesting an ASPPC. A full inflammatory work-up revealed highly positive titers of rapid plasma regain (RPR) and fluorescent treponemal antibody absorption (FTA-Abs), suggesting a syphilis infection. The ophthalmological manifestations dramatically improved after the patient was admitted for high-dose intravenous penicillin G 24 million per day for 2 weeks. CONCLUSION: This is the first case that reports an ocular syphilitic infection masquerading as MEWDS at presentation and that turns to be an ASPPC. Syphilis serology should be routinely done in every case of atypical MEWDS especially when unusually presented in a young healthy man, with bilateral involvement and a bad clinical evolution.

12-year analysis of incidence, microbiological profiles and in vitro antimicrobial susceptibility of infectious keratitis: the Nottingham Infectious Keratitis Study.

BACKGROUND/AIMS: To examine the incidence, causative microorganisms and in vitro antimicrobial susceptibility and resistance profiles of infectious keratitis (IK) in Nottingham, UK. METHODS: A retrospective study of all patients who were diagnosed with IK and underwent corneal scraping between July 2007 and October 2019 (a 12-year period) at a UK tertiary referral centre. Relevant data, including demographic factors, microbiological profiles and in vitro antibiotic susceptibility of IK, were analysed. RESULTS: The estimated incidence of IK was 34.7 per 100 000 people/year. Of the 1333 corneal scrapes, 502 (37.7%) were culture-positive and 572 causative microorganisms were identified. Sixty (4.5%) cases were of polymicrobial origin (caused by ≥2 different microorganisms). Gram-positive bacteria (308, 53.8%) were most commonly isolated, followed by Gram-negative bacteria (223, 39.0%), acanthamoeba (24, 4.2%) and fungi (17, 3.0%). Pseudomonas aeruginosa (135, 23.6%) was the single most common organism isolated. There was a significant increase in Moraxella spp (p<0.001) and significant decrease in Klebsiella spp (p=0.004) over time. The in vitro susceptibilities of Gram-positive and Gram-negative bacteria to cephalosporin, fluoroquinolone and aminoglycoside were 100.0% and 81.3%, 91.9% and 98.1%, and 95.2% and 98.3%, respectively. An increase in resistance against penicillin was observed in Gram-positive (from 3.5% to 12.7%; p=0.005) and Gram-negative bacteria (from 52.6% to 65.4%; p=0.22). CONCLUSION: IK represents a relatively common and persistent burden in the UK and the reported incidence is likely underestimated. Current broad-spectrum antimicrobial treatment provides a good coverage for IK, although challenged by some level of antimicrobial resistance and polymicrobial infection.

Cross-Linking Assisted Infection Reduction (CLAIR): A Randomized Clinical Trial Evaluating the Effect of Adjuvant Cross-Linking on Bacterial Keratitis.

PURPOSE: To determine whether there is a benefit to adjuvant corneal cross-linking (CXL) for bacterial keratitis. METHODS: This is an outcome-masked, randomized controlled clinical trial. Consecutive patients presenting with a smear-positive bacterial ulcer at Aravind Eye Hospitals at Madurai, Pondicherry, and Coimbatore in India were enrolled. Study eyes were randomized to topical moxifloxacin 0.5% or topical moxifloxacin 0.5% plus CXL. The primary outcome of the trial was microbiological cure at 24 hours on repeat culture. Secondary outcomes included best spectacle corrected visual acuity at 3 weeks and 3 months, percentage of study participants with epithelial healing at 3 weeks and 3 months, infiltrate and/or scar size at 3 weeks and 3 months, 3-day smear and culture, and adverse events. RESULTS: Those randomized to CXL had 0.60 decreased odds of culture positivity at 24 hours (95% confidence interval [CI]: 0.10-3.50; P = 0.65), 0.9 logarithm of the minimum angle of resolution lines worse visual acuity (95% CI: -2.8 to 4.6; P = 0.63), and 0.41-mm larger scar size (95% CI: -0.48 to 1.30; P = 0.38) at 3 months. We note fewer corneal perforations or need for therapeutic penetrating keratoplasty in the CXL group. CONCLUSIONS: We were unable to confirm a benefit to adjuvant CXL in the primary treatment of moderate bacterial keratitis. However, CXL may reduce culture positivity and complication rates; therefore, a larger trial to fully evaluate this is warranted. TRIAL REGISTRATION: NCT02570321.

Corynebacterium Species of the Conjunctiva and Nose: Dominant Species and Species-Related Differences of Antibiotic Susceptibility Profiles.

PURPOSE: Nondiphtherial Corynebacterium species are normal residents of human skin and mucosa, including the conjunctiva and nose, but can cause conjunctivitis and keratitis. Recently, resistance against various classes of antibiotics has been reported in Corynebacterium. The present study investigated the type of species and antibiotic susceptibilities of the conjunctival and nasal Corynebacterium species. METHODS: This study examined 183 strains of Corynebacterium species that were isolated from patients undergoing preoperative examinations for cataract surgery. Species were identified by RNA polymerase ß-subunit-encoding gene (rpoB) sequencing. Antibiotic susceptibility tests were performed by the microdilution method according to the Clinical and Laboratory Standards Institute standard method M45. RESULTS: Corynebacterium macginleyi was the most predominant species (84%; 46 of 55) in the conjunctiva. The 2 major species in the nasal cavity were Corynebacterium accolens and Corynebacterium propinquum (44% and 31%, respectively), followed by Corynebacterium pseudodiphtheriticum (8%), Corynebacterium jeikeium (7%), and C. macginleyi (3%). In contrast to other nasal Corynebacterium species, only C. macginleyi showed a high susceptibility to macrolides. However, among nonconjunctival Corynebacterium species, C. propinquum, was unique in having a high resistance rate to levofloxacin (29%), comparable with that observed in C. macginleyi (36%). Penicillin G and tobramycin showed good susceptibility in almost all strains. CONCLUSIONS: Drug resistance against fluoroquinolones and macrolides was observed in Corynebacterium species, with the antibiotic susceptibility profiles correlating with differences of the species and niche. Nasal and conjunctival Corynebacterium profiles of drug resistance suggest habitat segregation strictly at the species level.

Efficacy of a Novel Ophthalmic Antimicrobial Drug Combination Toward a Large Panel of Staphylococcus aureus Clinical Ocular Isolates From Around the World.

PURPOSE: Staphylococcus aureus is a leading cause of keratitis requiring urgent antimicrobial treatment. However, rising antibiotic resistance has rendered current ophthalmic antibiotics increasingly ineffective. First, a diverse, ocular S. aureus strain set was evaluated for resistance to 6 commonly used ophthalmic antibiotics. Next, a recently discovered antimicrobial drug combination containing polymyxin B/trimethoprim (PT) + rifampin that displayed impressive efficacy toward S. aureus in both in vitro and in vivo studies was evaluated as a potential novel keratitis therapeutic through testing this combination's efficacy against the clinical strain set. METHODS: A total of 163 S. aureus isolates were collected either commercially or from the Flaum Eye Institute, University of Rochester. The minimum inhibitory concentrations of moxifloxacin, levofloxacin, vancomycin, erythromycin, tobramycin, rifampin, and PT were determined for the entire strain set to establish the incidence of resistance to current treatment options among a contemporary clinical isolate set and compared with the performance of PT + rifampin. RESULTS: Among all 163 isolates tested, high rates of antibiotic resistance were found toward erythromycin (69% resistance), moxifloxacin (33%), levofloxacin (40%), and tobramycin (17%). Conversely, the entire strain set, including multidrug resistant isolates, was sensitive to PT + rifampin, demonstrating the potency of this combination. CONCLUSIONS: We established that antibiotic resistance is pervasive among clinical S. aureus isolates, underscoring the concern for the effectiveness of current ophthalmic antibiotics. The drug combination of PT + rifampin, however, eradicated 100% of isolates tested, demonstrating the ability to overcome existing circulating resistance factors, and as such, might represent a promising therapeutic for S. aureus keratitis.

Methicillin-Resistant Staphylococcus aureus Keratitis: Initial Treatment, Risk Factors, Clinical Features, and Treatment Outcomes.

PURPOSE: To analyze the clinical characteristics, management choices, and outcomes of cases of methicillin-resistant Staphylococcus aureus (MRSA) keratitis. DESIGN: Retrospective interventional case series. METHODS: Fifty-two culture-proven (52 eyes) cases of MRSA keratitis diagnosed and treated at the University of Pittsburgh Medical Center were identified and reviewed. RESULTS: The mean age was 66.6 ± 19.2 years with a median follow-up time of 147 days. The most prevalent risk factors included a history of ocular surgery (62.5%), topical corticosteroid use (35.4%), and dry eye syndrome (37.5%). There was a high burden of systemic disease (95.8%). The average presenting logarithm of minimal angle of resolution visual acuity was 1.7 ± 0.8 and the average final logarithm of minimal angle of resolution visual acuity was 1.2 + 1.0. Initial antibiotic treatment varied, with 20.8% receiving moxifloxacin alone, 20.8% receiving fortified cefazolin and fortified tobramycin together, and 12.5% receiving fortified vancomycin and fortified tobramycin, although other antibiotics were used during treatment if warranted. Surgical management was often required as 17.3% of eyes perforated: 13.5% required tarsorrhaphy, 5.8% required penetrating keratoplasty, and 1 eye was enucleated. When patients treated with fourth-generation fluoroquinolones were compared with those treated with fortified vancomycin, no difference in final visual acuity, treatment duration, or need for surgery was found. CONCLUSION: MRSA causes fulminant keratitis often requiring surgical management with poor visual acuity outcomes. Poor ocular surface, topical corticosteroid use, previous ocular surgery, and/or a high burden of systemic disease were identified as common risk factors. Patients treated with fluoroquinolones in our study had comparable outcomes to those treated with fortified vancomycin; however, those treated with fortified vancomycin tended to have more severe ulcers at presentation.

Validation of a Comprehensive Clinical Algorithm for the Assessment and Treatment of Microbial Keratitis.

PURPOSE: To validate a comprehensive clinical algorithm for the assessment and treatment of microbial keratitis (MK). DESIGN: Retrospective cohort study. METHODS: The "1, 2, 3 Rule" for the initial management of MK was conceived by Vital and associates in 2007 to inform the decision as to when to perform corneal cultures. The rule is invoked when any 1 of 3 clinical parameters is met: ≥1+ anterior chamber cells, ≥2 mm infiltrate, or infiltrate ≤3 mm distance from the corneal center. When the rule is met, we added the mandatory use of fortified topical antibiotics after cultures are obtained. We compared outcomes of cases presenting to Massachusetts Eye and Ear 2 years before (Group I, n = 665) and after (Group II, n = 767) algorithm implementation. The primary composite outcome was a vision-threatening complication, such as corneal perforation. RESULTS: At a median follow-up of 67.0 and 60.0 days, respectively, 172 patients experienced a vision-threatening complication (Group I, 12.9% vs Group II, 11.2%, P = .51). While the algorithm codified conventional management practice at either end of disease severity, the effect of algorithm-augmented care was best appreciated in patients with lesions satisfying only 1 criterion. In this group, there was an increase in the proportion of patients undergoing culture at presentation (54.6% vs 67.7%, P = .006), fortified antibiotic prescription (29.7% vs 53.9%, P < .001), and reduction in vision-threatening complications (9.7% vs 1.8%, P = .001). The proportion of patients who were not cultured at presentation but later required culturing decreased (13.4% vs 5.1%, P = .001), as did patients who did not meet any criteria but were nonetheless cultured (23.9% vs 8.5%, P < .001). Multiple logistic regression showed that all algorithm parameters were independently associated with outcome: ≥1+ anterior chamber cells (odds ratio [OR] 1.66, 95% confidence interval 1.09-2.52); ≥2 mm infiltrate (OR 4.74, 2.68-8.40); and ≤3 mm from corneal center (OR 2.82, 1.85-4.31), confirmed with comparison to a bootstrapped sample (n = 10,000). CONCLUSIONS: The implementation of this algorithm reduced vision-threatening complications for patients with lesions satisfying only 1 criterion, arguably the most difficult patients in whom to judge disease severity. Implementation also led to a decrease in patients receiving unnecessary care.