Background/Objectives: To evaluate ocular disease and eye care utilization among adults with vitamin A deficiency (VAD) in a high-resource healthcare setting, with particular emphasis on nutritional etiologies, clinical nutrition oversight, and outcomes associated with severity of deficiency. Methods: A retrospective chart review was conducted at Dartmouth Hitchcock Medical Center (DHMC) from 1 January 2019 through 31 December 2022. Adults (>18 years) with measured serum retinol concentrations were identified, and data were extracted on retinol concentration, diagnosis, referring service, and vital status. Patients with VAD (serum retinol <32.5 µg/dL per our laboratory threshold) underwent detailed chart review, including social determinants of health and documented nutritional risk factors. For patients with VAD who received an ophthalmologic evaluation, slit lamp findings, ocular symptoms, duration of deficiency, and vitamin A treatment were assessed. Results: VAD was identified in 752 of 2725 patients (27.7%) tested for VAD, and 330 patients had concentrations below the World Health Organization (WHO) threshold for VAD (<20 µg/dL). Hepatic, nutritional, and malabsorptive conditions were prominent contributors, including cirrhosis related to alcohol use or hepatitis C virus (30%), malnutrition or malabsorption following bariatric surgery (24%), and pancreatic insufficiency (20.1%). Food insecurity data were incomplete but showed no significant association with vitamin A concentration. Despite biochemical evidence of deficiency, only 72 patients with VAD (9.6%) underwent ophthalmologic evaluation, and only three were referred specifically due to VAD. Clinical signs or symptoms consistent with xerophthalmia were observed in 21% of those evaluated, and 18% demonstrated corneal findings. Vitamin A supplementation was documented in just over half of symptomatic patients, with objective or symptomatic improvement noted in three cases. VAD was explicitly acknowledged in only 9.7% of ophthalmology notes. Increasing severity of VAD was strongly associated with mortality (p < 0.001), independent of food insecurity, which showed no association with serum retinol concentrations. Conclusions: In this high-resource clinical setting, VAD is common in an at-risk population and largely driven by nutrition-related disease states affecting absorption, metabolism, and hepatic storage. Despite clear biochemical deficiency and associated mortality risk, VAD is underrecognized, undertreated, and infrequently linked to ocular evaluation, highlighting a critical gap in nutrition-focused screening, interdisciplinary communication, and proactive vitamin A assessment in medically complex adults.

PURPOSE. The 2023 Pseudomonas aeruginosa keratitis outbreak linked to contaminated artificial tears underscored the need for new therapies against extensively drug-resistant ocular pathogens. In vitro data suggested additive or synergistic activity between the siderophore-cephalosporin cefiderocol (FDC) and either moxifloxacin (MOX) or polymyxin B sulfate (PB). Here, we tested whether combining FDC with the commercial formulations of MOX (0.5%) or PolyTrim (PT; PB 10,000 U/mL + trimethoprim 0.1%) improved in vivo outcomes. METHODS. New Zealand White rabbits were injected intrastromally with 5000 CFU of Pseudomonas aeruginosa strain CDC1270. After 16 hours, established infections were treated every 30 minutes for 8 hours with FDC, followed 5 minutes later by MOX or PT. Additional groups received monotherapies or saline. Bacterial burden (CFU/cornea) and anterior chamber cultures were determined, and ocular inflammation was assessed. RESULTS. FDC + MOX reduced bacterial burden by 2.8 log10 CFU, outperforming FDC and MOX monotherapies, although no eyes were sterilized. PT monotherapy produced a significant 3.2 log10 reduction in CFU. The FDC + PT combination yielded the most potent activity, with almost 6.9 log10 reduction and sterilization of 10 of 12 corneas. Notably, anterior chamber invasion occurred in saline and MOX groups but in none of the FDC-containing groups, and perforations were absent in all FDC and PT treatments. CONCLUSIONS. FDC + PT was superior to monotherapies and to FDC + MOX, achieving frequent sterilization and preventing intraocular spread and corneal perforations. These data support PT alone or in combination with FDC as promising therapeutic candidates for the treatment of XDR P. aeruginosa keratitis.

INTRODUCTION:To compare cataract surgical outcomes and rates of complications between attending-led and resident-led surgical cases before and after the introduction of senior Dartmouth ophthalmology residents into the operating room at the White River Junction Veterans Affairs Medical Center (WRJ VA) in 2023. MATERIALS AND METHODS:Preoperative patient factors, intraoperative metrics, and postoperative outcomes of patients who underwent eye surgery between July 1, 2022 and June 30, 2024 were recorded. Statistics were run to compare the 2022-2023 year (year 1) with a single attending surgeon to the 2023-2024 year (year 2) with the addition of 2 senior residents. Statistical tests also compared metrics and outcomes between the 3 surgeons in year 2. RESULTS:There was no significant difference in intraoperative complications or visual outcomes with the addition of residents as primary surgeons. Resident-led cases were longer on average, but the overall number of surgeries performed did not decrease with the addition of residents. The attending tended to do more of the cases in which the patient exhibited preoperative factors that could potentially contribute to complication or reduce visual outcomes, but there was no difference in intraoperative metrics across the 3 surgeons. CONCLUSIONS:Introducing resident training into a surgical service is safe and does not reduce the quality of patient outcomes. These findings support the WRJ VA-Dartmouth partnership as a model for implementing supervised resident surgical education and highlight how VA-based training environments can simultaneously advance high-quality veteran care and graduate medical education.

Purpose:The 2023 outbreak of Pseudomonas aeruginosa keratitis linked to contaminated artificial tears highlighted the need for new treatments targeting ocular infections caused by multi-drug-resistant and extensively drug-resistant bacteria. This study evaluated the in vitro efficacy and potential synergy of cefiderocol and moxifloxacin against P. aeruginosa keratitis isolates. The influence of quorum-sensing defects on antibiotic efficacy was also assessed because of the increase in lasR mutant keratitis isolates. Ceftazidime, which lacks the "Trojan Horse" iron-binding-mediated bacterial entry mechanism of cefiderocol, served as a comparator. Methods:Time-kill and epsilometer (E-test) assays were used to determine minimum inhibitory concentrations and drug interactions. Fractional inhibitory concentration indices were calculated to characterize drug interactions as antagonistic, indifferent, additive, or synergistic. Quorum-sensing defective strains were identified by a characteristic colony sheen phenotype associated with LasR system defects. Results:Time-kill studies demonstrated consistent synergistic interactions between cefiderocol and moxifloxacin against seven out of seven tested P. aeruginosa keratitis isolates, including one from the 2023 outbreak. E-test-based assays showed additive or synergistic activity against 79% of isolates, although this dropped to 60% among suspected quorum-sensing defective strains. In contrast, the ceftazidime and moxifloxacin combination was less effective, particularly sheen-positive strains. The cefiderocol-moxifloxacin combination showed indifferent effects against Serratia marcescens and Staphylococcus aureus, with each antibiotic retaining individual activity. Conclusions:Cefiderocol and moxifloxacin exhibited synergy against most tested P. aeruginosa keratitis isolates in vitro, including those with suspected quorum-sensing defects. These findings support further investigation of this combination for treating highly drug-resistant ocular infections.

Fungal keratitis is a severe corneal infection most commonly caused by filamentous fungi. Even with prompt treatment with current antifungals, it often results in corneal perforation and blindness. In this report, we observe that the beta-adrenergic antagonist, propranolol, displays antifungal activity against Aspergillus and Fusarium corneal isolates in vitro and strikingly blocks disease establishment in a murine model of Aspergillus fumigatus keratitis. These findings suggest that beta-blockers have potential as a novel FK treatment.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT00997035 (MUTT Trial).

Purpose:Antibiotic combination therapy is commonly used for empiric treatment of microbial keratitis, a potentially blinding infection of the cornea. Pseudomonas aeruginosa (P. aeruginosa) is a major cause of severe keratitis, and the 2023 outbreak linked to artificial tears involved a strain resistant to aminoglycosides and fluoroquinolones, resulting in widespread vision loss. Despite various proposed treatments, no consensus exists for management of keratitis caused by the outbreak strain. The purpose of this study was to evaluate the efficacy of cefiderocol (FDC) combined with polymyxin B (PB) against ocular P. aeruginosa keratitis isolates, including extensively drug-resistant (XDR) strains from the 2023 artificial tear-associated outbreak. Methods:Time-kill assays and epsilometer (E-test) synergy testing were performed on a panel of keratitis isolates. Genetic analysis was conducted on mutants with reduced FDC susceptibility. Results:Time-kill assays demonstrated synergy for two XDR outbreak isolates (P < 0.05), whereas the E-test used across diverse keratitis isolates showed additive to indifferent interactions. Quorum-sensing-deficient, sheen-positive strains showed reduced responsiveness (P < 0.01). Non-antagonistic interactions were observed for Serratia marcescens (S. marcescens) and Staphylococcus aureus (S. aureus) keratitis isolates, with synergy for some S. marcescens strains. Mutants with reduced FDC susceptibility harbored mutations in baeS and fepA, yet remained responsive to the antibiotic combination. Conclusions:FDC combined with PB demonstrates promising activity against drug-resistant Gram-negative keratitis pathogens, including XDR P. aeruginosa. Translational Relevance:These findings support the further development of FDC with PB as a candidate therapy for drug-resistant ocular infections.

OBJECTIVES:To present an 11-year case series of pterygia. METHODS:We conducted a retrospective case review of all pterygium surgeries performed at Dartmouth Hitchcock Medical Center between April 2011 and July 2022. Eighty-six cases were identified through a chart review identifying procedures with the code «Excision of Pterygium W/Transplant» on our electronic medical record system, obtained per a protocol approved by the Dartmouth-Hitchcock Health Human Research Protection Program (IRB study 02002030). RESULTS:Of 86 cases, 84 were performed with conjunctival autografting (CAG) with fibrin glue, one was performed with just amniotic membrane transplant (AMT) with fibrin glue, and one was performed with both CAG and AMT with fibrin glue. No intraoperative mitomycin C or 5FU were used. Three patients with postoperative complications were identified, including two cases of postoperative conjunctival granulomas and one case of recurrent pterygium. Both conjunctival granulomas were treated with surgical excision without recurrence and sent to pathology for analysis. Histopathological findings are discussed herein. The recurrent pterygium was treated with 5FU injections, after which there were minimal symptoms and no progression at the last follow-up. CONCLUSIONS:Although recurrence is the most commonly discussed complication of pterygium surgery, in our cases, over an 11-year span, we found that postoperative conjunctival granulomas were more common than recurrence.

PURPOSE:The 2023 outbreak of extensively drug resistant (XDR) Pseudomonas aeruginosa (PA) eye infections was linked to the use of non-preserved, multi-use artificial tears purchased online. The lack of preservatives has been attributed to be the predominant factor in the outbreak. This led us to the current study for which the goal was to determine whether common ophthalmic preservatives could eliminate the outbreak XDRPA and other PA keratitis isolates. MATERIALS AND METHODS:Time-kill studies were performed in Mueller-Hinton broth (MHB) and phosphate buffered saine (PBS) on 3 PA strains including the XDRPA outbreak strain. Preservatives assessed were benzalkonium chloride (BAK) 0.04%, 0.01%, and 0.004%, Polyquaterium-1 (Polyquad) (PQ) 0.001%, Sodium Perborate (SP) 0.1%, and EDTA 0.1%. In addition, time-kill assays were performed using preserved and a non-preserved commercially-available artificial tears. RESULTS:BAK 0.04% and 0.01%, and PQ eliminated all PA isolates in both media after 4 h. BAK 0.004% and SP eliminated all PA strains in PBS at 1 h but did not produce bactericidal 99.9% decreases in MHB over 24 h. EDTA did not produce a bactericidal effect in either media. Artificial tears containing sorbic acid 0.25% and edetate disodium 0.1%, PQ, SP, and PURITE eliminated the PA strains within 24 h. CONCLUSIONS:Several common preservatives were effective in eliminating PA strains including the outbreak strain CDC1270. Preservative efficacy was delayed or inhibited in rich media (MHB) compared to PBS. These results suggest that the 2023 outbreak could have been prevented by using a common preservative in the artificial tears.

Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (<60 years or ≥60 years) and disease duration (recent [<6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, −20.8% to 25.8%]; P>.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months (P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, −3.39 months [95% CI, −6.73 to −0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. ClinicalTrials.gov Identifier: NCT03134196

High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care. To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point). The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (<60 years vs ≥60 years) and disease duration (<6 months vs ≥6 months). A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo. The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK. A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02). Although the primary outcome did not show a benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO. ClinicalTrials.gov Identifier: NCT03134196

PURPOSE:The Zoster Eye Disease Study (ZEDS) is a multicenter randomized clinical trial (RCT) funded by the National Eye Institute aiming to determine the efficacy of suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) that enrolled fewer participants than planned (527/780, 67.6%). Understanding reasons for nonparticipation of likely eligible prescreened patients provides insights into patient populations that are not represented by ZEDS and barriers in clinical trials. METHODS:In this retrospective cohort study, HZO adults likely eligible for ZEDS with a history of a typical rash and a medical record within the past year of an episode of epithelial or stromal keratitis or iritis were prescreened at activated Participating Clinical Centers from 2017 to 2022 using a standard prescreening log. De-identified data including demographic information, reasons for exclusion because of ineligibility, and patient refusal were retrospectively entered into REDCap and analyzed. RESULTS:Prescreening logs with reasons for nonconsent (1244/1706, 72.9%) were included in the data set. Patients were excluded from the study (915/1244, 73.6%) because they did not meet all inclusion criteria (619/915, 67.7%) or met an exclusion criterion (296/915, 32.3%). Among the 12 exclusion criteria for the ZEDS study, immunocompromise (76/296, 25.7%) and renal insufficiency (50/296, 16.9%) were most frequently reported. Patient refusal to participate (327/1,244, 26.3%) was common. CONCLUSION:The most common reasons for ineligibility were immunocompromise and renal insufficiency. There may be benefits to long-term antiviral use in these populations not captured in ZEDS. A quarter (26.3%) of prescreened patients refused participation, showing the substantial impact of patient preferences on trial participation.

Background/Objectives: Endophthalmitis is an intraocular microbial infection that can lead to permanent blindness, even with prompt anti-microbial therapy. Multi-drug-resistant organisms are on the rise, potentially limiting the efficacy of current empiric antibiotic therapies of intravitreal ceftazidime and vancomycin. Cefiderocol is a recent FDA- and EMA-approved antibiotic for multi-drug-resistant Gram-negative bacteria. Methods: To better understand its potential utility in the treatment of ocular infections, the MIC of cefiderocol was compared to ceftazidime and amikacin in endophthalmitis bacterial isolates using Epsilometer testing. Because vancomycin is commonly given concomitantly as part of empiric endophthalmitis treatment, possible synergistic and antagonistic effects of concomitant vancomycin and cefiderocol were also evaluated. Results: Cefiderocol was found to have lower MIC values compared to ceftazidime for Pseudomonadales or Enterobacterales species. When comparing the MICs of cefiderocol and vancomycin, there appeared to be no antagonism between the two antibiotics. Conclusions: This is the first report exploring the use of cefiderocol in endophthalmitis strains. The results of this study show this is a promising antibiotic for multi-drug-resistant Gram-negative organisms but further research is needed to investigate its intraocular safety profile.

ABSTRACT Pseudomonas aeruginosa causes severe vision threatening keratitis. LasR is a transcription factor that regulates virulence associated genes in response to the quorum sensing molecule N-3-oxo-dodecanoyl-L-homoserine lactone. P. aeruginosa isolates with lasR mutations are characterized by an iridescent high sheen phenotype caused by a build-up of 2-heptyl-4-quinolone. A previous study indicated a high proportion (22 out of 101) of P. aeruginosa keratitis isolates from India between 2010 and 2016 were sheen positive and had mutations in the lasR gene, and the sheen phenotype correlated with worse clinical outcomes for patients. In this study, a longitudinal collection of P. aeruginosa keratitis isolates from Eastern North America were screened for lasR mutations by the sheen phenotype and sequencing of the lasR gene. A significant increase in the frequency of isolates with the sheen positive phenotype was observed in isolates between 1993 and 2021. Extracellular protease activity was lower among the sheen positive isolates and a defined lasR mutant. Cloned lasR alleles from the sheen positive isolates were loss of function or dominant negative and differed in sequence from previously reported ocular lasR mutant alleles. Insertion elements were present in a subset of independent isolates and may represent an endemic source from some of the isolates. Retrospective analysis of patient information suggested significantly better visual outcomes for patients with infected by sheen positive isolates. Together, these results indicate an increasing trend towards lasR mutations among keratitis isolates at a tertiary eye care hospital in the United States.

Abstract Objective Uveitis is an inflammatory process of the eye that can lead to severe vision loss. Non-infectious forms of uveitis constitute the majority of cases and chronic disease is typically treated with immunosuppressive drugs. A minority of uveitis cases are of an infectious cause, and in these cases, the use of immunosuppressive agents may aggravate the underlying infection. Design: Retrospective case series. Result. Five patients who initially presented with ocular findings suspicious for non-infectious uveitis and who were treated with corticosteroids. After failing to respond to corticosteroid therapy, and with a history of injection drug use (IDU) eventually reported by all five patients, there was a high degree of clinical suspicion for an underlying infectious process. All five were later classified as having endogenous endophthalmitis related to IDU, and experienced clinical improvement after antibiotic therapy and pars plana vitrectomy. Conclusions and Importance. Given the ongoing opioid crisis, this study demonstrates the importance of considering IDU-associated endogenous endophthalmitis in any individual with intraocular inflammation and history of IDU presenting with new-onset vision loss, irrespective of time since last reported use.

Purpose: To describe 3 adult cases of keratitis secondary to vitamin A deficiency (VAD) in relation to vitamin A levels Dartmouth-Hitchcock Medical Center (DHMC) population and published literature. Methods: Records of 3 patients with xerophthalmia were reviewed. All serum vitamin A levels obtained at DHMC during the same time period of our 3 cases (2019–2020) were analyzed. Outcomes were examined by age and range of deficiency. Results: Three patients, with short gut syndrome, chronic esophagitis, and alcohol use disorder, presented with xerophthalmia over 1 year. Serum vitamin A levels were 6.4 μg/dL, 16.1 μg/dL, and undetectable (<5.0 μg/dL), respectively (normal: 32.5–78.0 μg/dL). Findings ranged from conjunctival keratinization to corneal perforation. Corneal cultures in patient 3 grew methicillin-sensitive Staphylococcus aureus. The ocular surface improved significantly in 2 patients following vitamin A supplementation. Two patients died during treatment. Analysis of 1596 vitamin A levels at DHMC revealed 431 patients with VAD, including 158 levels at or below those of our presented symptomatic cases. Conclusions: Vitamin A deficiency can occur in adults in high resource settings and lead to severe ocular morbidities, and is commonly associated with comorbidities such as alcohol use disorder and gastrointestinal disease. Vitamin A supplementation improved ocular findings in 2 of our patients. VAD was identified in 431 patients at DHMC over one year, indicating a surprisingly large population of patients at risk for xerophthalmia.