Cheryl Guttman is a medical writer based in Deerfield, Ill.

Cheryl Guttman Krader, BS, Pharm

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This article was reviewed by Yusen Huang, MD



Adding cefuroxime to the irrigating solution used during cataract surgery appears to be a safe and effective method for reducing the risk of postoperative endophthalmitis, according to researchers who reported their experience with this technique in a recently published retrospective study.

The investigation included 61,299 eyes. Of the total cohort, 15,948 eyes were operated on between January 1, 2012, and December 31, 2014, using plain balanced salt solution (BSS) as the irrigating solution (control group), and 45,351 eyes underwent cataract surgery between January 1, 2015, and December 31, 2019, using irrigating solution that contained cefuroxime 1500 µg/mL. 

The mixture was prepared by withdrawing 10 mL BSS from the irrigating solution and injecting it into a vial of cefuroxime 750 mg. The reconstituted solution was injected back into the BSS container.

The rate of endophthalmitis was significantly decreased after the transition to intraoperative irrigation with cefuroxime. Endophthalmitis occurred in 11 eyes (0.07%) in the group that did not receive intraoperative cefuroxime and in 5 eyes (0.01%) when cefuroxime was used in the irrigating solution (

 < .01). 

Cultures were positive for bacteria in 4 of the 11 cases in the control group and in 1 of the 5 eyes in the intraoperative cefuroxime group (

 > .05). No safety issues were associated with intraoperative cefuroxime irrigation.

Discussing the research, Yusen Huang, MD, PhD, of the Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences in Qingdao, People’s Republic of China, pointed out that although intracameral antibiotics are already widely accepted as a method for endophthalmitis prophylaxis in patients undergoing cataract surgery, the optimal choice of prophylactic routes and antibiotics is controversial.

“In European countries, commercial cefuroxime formulation (Aprokam) has been widely used, and the dose administered is the same as in the European Society of Cataract and Refractive Surgeons (ESCRS) randomized prospective study demonstrating its efficacy,” Huang said. 

Surgeons have been reluctant to adopt intracameral cefuroxime because it is off-label and carries potential risks.

“In our study, the manner of cefuroxime preparation was modified so that it involved only a 1-step process. This makes it simpler, saves resources, and could reduce the potential risks of both preparation errors and contamination,” Huang pointed out. “Although the intracameral concentration achieved with our approach is estimated to be 1500 µg/mL, or only about 45% of the ESCRS recommendation, we found that it reduced the rate of postcataract surgery endophthalmitis by about sevenfold.”

Furthermore, Huang explained that “during the last 2 years in our hospital where more than 25,000 cases of cataract surgery have been performed using intraoperative cefuroxime irrigation, not a single patient developed endophthalmitis. 

It should be noted, however, that this method is not recommended for use in patients with a history of vitrectomy, [considering] the potential for rapid posterior segment diffusion of the antibiotic and potential macular toxicity.”

Although adding cefuroxime to the irrigating solution is still an off-label use of the medication, the authors suggested that it represents a good option for countries with no licensed product for intracameral use of endophthalmitis prophylaxis and particularly in developing regions where the risks for both endophthalmitis and a poor outcome may be higher given a variety of contributory factors.

Throughout the entire study period, all patients received the same preoperative antisepsis with application of topical povidone-iodine. 

In addition, all patients started using topical levofloxacin 0.5% solution preoperatively and continued it postoperatively, along with a topical steroid and topical nonsteroidal anti-inflammatory drug.


Postoperative follow-up visits were scheduled at 1 and 4 days, 4 weeks, and 12 weeks, but patients were instructed to seek care if they developed pain, redness, or loss of vision. 

The analyzed outcome was onset of acute-onset endophthalmitis, which was diagnosed if a patient presented within 6 weeks of surgery with eye pain, anterior chamber reaction or flare, hypopyon, and/or vitritis with causes for intraocular inflammation other than endophthalmitis excluded.

The 16 cases of endophthalmitis recorded during the 9-year study period developed at a median of 7.56 days after cataract surgery (range, 1-21 days). 

None of the cases occurred in a patient who had an intraoperative complication or was noted to have incision leakage at the time endophthalmitis was identified.

Isolates from the culture-positive cases of endophthalmitis in the control group included 

 was identified as the causative pathogen in the culture-positive case of endophthalmitis among patients who received intraoperative cefuroxime, and the organism was found susceptible to cefuroxime.


1. Ma X, Zie L, Huang Y. Intraoperative irrigation prophylaxis for acute-onset endophthalmitis after phacoemulsification surgery. 

Articles

Findings from retrospective study support intraoperative cefuroxime irrigation.  


Reducing post-cataract surgery endophthalmitis: Investigators focus on therapeutic regimen

Results from a laboratory study measuring oxygen kinetics during corneal crosslinking (CXL) indicate that supplementary oxygen has the potential to substantially increase the efficacy of the procedure, according to Theo G. Seiler Jr, MD.

The laboratory study, which was performed using de-epithelialized porcine eyes, measured local oxygen concentrations at varying corneal depths under atmospheric (21% O2) and hyperoxygenic (100% O2) conditions with different levels of UV irradiation. 

Benefits of topography-guided treatments for irregular corneas

The analyses showed that compared with the atmospheric oxygen environment, supplementary oxygen increased the amount of oxygen available in the stroma during CXL. 

The benefit of the hyperoxygenic environment was particularly seen when using higher UV irradiances that are associated with increased oxygen consumption, noted Seiler, senior physician in the Department of Ophthalmology at the University of Bern in Switzerland.

“The mechanism of action for CXL involves UV-induced activation of riboflavin, the photosensitizer, resulting in the generation of reactive oxygen species that induce formation of covalent bonds within the collagen fibrils and crosslink the proteoglycans between the collagen fibrils,” he said. “Many previous studies have investigated the influence of varying the parameters for riboflavin imbibition and UV irradiation on CXL effectiveness.”

Seiler said the study was motivated by the limited research investigating the role of oxygen that is the third crucial factor for achieving sufficient CXL. 

Corneal crosslinking outcomes look good for pediatric keratoconus

“Our findings show that providing supplementary oxygen is likely to be beneficial by increasing the aerobic reaction and allowing more efficient CXL in deeper corneal layers and at UV irradiance levels less than 3 mW/cm2,” he said.

Measurement of the oxygen concentration at different corneal depths was accomplished by inserting a fiber probe into channels created by a femtosecond laser at depths of 100 μm, 200 μm, and 300 μm. 

Eyes were exposed to 0.1% riboflavin (Vibex Rapid; Avedro/Glaukos) for 10 minutes, and then the oxygen concentration was continuously measured during irradiation at 3, 9, 18, and 30 mW/cm2. 

“In order not to alter the cornea during the measurements, the used fiber probe had a tip that was only around 50 μm in diameter,” Seiler said.

Groups of 8 eyes each were evaluated under each of the testing conditions while the oxygen concentration was continuously measured. 

Under atmospheric oxygen and with irradiation at 3 mW/cm2, representing the conventional Dresden protocol, there was a surplus of oxygen available at all measured depths during the entire CXL procedure. 

However, when the irradiance was increased to 9 mW/cm2, sufficient oxygen for CXL was available only at 100 μm and 200 μm. 

At UV-irradiance above 9 mW/cm2, all oxygen was consumed within the anterior 100 μm, indicating that there was insufficient oxygen for achieving sufficient crosslinking in the profound cornea, Seiler said.

When the testing was done in the hyperoxygenic environment, there was sufficient oxygen available for crosslinking at all measured depths when using the 3 mW/cm2 and 9 mW/cm2 irradiances.

At higher UV irradiances, there was more oxygen available than under atmospheric conditions, although still not enough to provide sufficient oxygen through the entire corneal stroma. 

Corneal transplantation experiences a revolution

Additional analyses determining the consumption of oxygen showed that during the procedure, the half-lives were longer and the depletion rates higher with supplementary oxygen, suggesting a more efficient CXL than under atmospheric oxygen conditions, said Seiler.


This article is based on a presentation given by Seiler at the 2020 ESCRS Virtual Congress. The study was published (Seiler TG et al. Am J Ophthalmol. 2020;223:368-376). Seiler has no relevant financial interests to disclose.

Ex vivo experiment identifies potential benefit for supplementary oxygen.

Maximizing CXL effectiveness


Findings from a series of preclinical and retrospective clinical studies suggest the rho-kinase inhibitor (ROCKi) netarsudil (Rhopressa; Aerie Pharmaceuticals) may be the preferred treatment for steroid-induced ocular hypertension (OHT).

As reported in a recently published article [Li G, et al. 

. 2021Mar 30;10:e60831], the research showed that netarsudil effectively prevented and reduced steroid-induced OHT in an animal model. 

In addition, analyses of in vivo spectral domain 

 (SD-OCT) images and from histologic examination of tissue from sacrificed animals revealed that the ROCKi attenuated steroid-induced pathologic changes in the conventional outflow pathway.

Rho kinase inhibitors: Filling a gap in glaucoma treatment

The benefits observed in the animal model were corroborated by the results of retrospective clinical studies showing reductions of IOP were achieved upon initiation of netarsudil among 2 independent cohorts of patients with steroid-induced OHT that was refractory to standard 

W. Daniel Stamer, PhD, is a professor of ophthalmology at Duke University in Durham, North Carolina, where he directs a research laboratory focusing on the pathobiology of OHT in 

“It is well known that steroids interfere with aqueous outflow through the conventional pathway by increasing extracellular matrix deposition, cell contractility, and tissue stiffness,” he said. “Now our group has shown for the first time that it is possible to reverse those changes using a medication that directly targets cells in the conventional outflow pathway.”

Pratap Challa, MD, a glaucoma specialist and associate professor of ophthalmology, Duke University, said the studies show that netarsudil has strong potential to treat steroid-induced 

, particularly because steroids increase outflow resistance at the level of the trabecular meshwork and netarsudil acts directly on this tissue.

Taking a step forward in glaucoma patient care

“Ideally, a benefit of netarsudil for treating or preventing steroid-induced OHT should be established based on randomized prospective clinical trials,” Challa said. “It seems reasonable based on the available evidence, however, that clinicians might strongly consider using netarsudil for IOP lowering in patients who are steroid responders.”



Stamer and colleagues conducted their preclinical studies using a mouse model of steroid-induced OHT in which an implant containing dexamethasone-loaded nanoparticles is injected subconjunctivally.

“We demonstrated previously that this treatment predictably results in IOP elevation and in the same characteristic morphological changes that are seen in human eyes with steroid-induced OHT,” Stamer said.

The activity of netarsudil for countering steroid-induced IOP elevations was shown in 2 experiments. 

In one study, netarsudil or placebo was administered as a preventive intervention beginning 1 day prior to steroid delivery and continued for 4 weeks to cover the duration of steroid exposure from implant release. 

The second study investigated netarsudil as a therapeutic modality to reverse steroid-induced changes. In this second experiment, netarsudil or placebo were started 3 weeks after steroid delivery.

Tissue effects of netarsudil treatment were investigated in the latter group of animals and demonstrated reversal of the outflow dysfunction and associated extracellular matrix deposition and fibrotic changes. 

These studies included a novel approach for estimating trabecular meshwork stiffness that applied inverse finite element modeling to SD-OCT images. 

The findings were confirmed through direct measurements obtained using atomic force microscopy.

“It was especially noteworthy that the trabecular meshwork regained normal biomechanical properties and exhibited significant improvement in extracellular matrix morphology within 4 days after the animals were started on netarsudil treatment,” Stamer said.

Drainage device offers IOP lowering capabilities at 1 year


The activity of netarsudil as treatment for steroid-induced OHT was investigated by identifying cohorts of patients who were refractory to conventional IOP-lowering medications. 

The first series of patients was identified through a retrospective search of the electronic medical record system at the Duke Eye Center. 

It included 21 eyes of 19 patients whose steroid-induced OHT failed to respond to aqueous humor suppressors (carbonic anhydrase inhibitors and/or adrenergics) and in some cases, prostaglandin analogue treatment as well.

Mean IOP at baseline (prior to starting netarsudil) was 24.3 mm Hg. At 1 month after starting netarsudil and without any tapering of the steroid dose, mean IOP decreased to 16.4 mm Hg.

The second cohort of patients was derived from a retrospective chart review of patients seen by glaucoma specialist John R. Samples, MD, with NVISION Eye Center in Portland, Oregon. 

A menu of glaucoma treatments includes options to fit all scenarios

It included 11 eyes of 8 patients. Mean IOP in this group was 26.5 mm Hg prior to starting netarsudil, and it was reduced to 19.5 mm Hg with the use of netarsudil.


Going forward, Stamer and colleagues are collaborating with Felipe Medeiros, MD, PhD, professor of ophthalmology at Duke University, and Ross Ethier, PhD, professor of biomedical engineering at Georgia Tech, to develop the SD-OCT imaging-based approach as a clinical tool for functional evaluation of the conventional outflow system in patients with POAG.

“With steroid-induced OHT, we know that it might be possible to intervene with medication before the steroid-induced fibrotic changes become permanent, but the status of the conventional outflow pathway is more of an unknown in the larger population of patients with POAG,” Stamer concluded. “A method for assessing the function of the conventional outflow system might help clinicians individualize treatment decisions with regard to a role for ROCKi treatment and it could also be used for monitoring treatment.” 


Stamer has received research support from Aerie Pharmaceuticals, Aerpio, Allergan, Bausch + Lomb, Broadwing Bio, Editas Medicine, and Regeneron, serves on scientific advisory boards for Aerpio, Broadwing Bio, Glauconix, and Qlaris, and has stock options in Glauconix and Qlaris.

Challa owns equity in Aerie Pharmaceuticals.

Measurements from multiple studies show benefits of rho-kinase inhibition.

Research: Treatment targets steroid-induced OHT

This article was reviewed by Raj K. Maturi, MD

The integrin antagonist, THR-687 (Oxurion), showed promising efficacy as a treatment for 

in a multicenter phase 1 clinical trial, said Raj K. Maturi, MD, at the 2020 American Academy of Ophthalmology virtual annual meeting.

The open-label, nonrandomized, dose-escalating study (NCT03666923) enrolled 12 patients who were followed for 3 months after receiving 1 intravitreal injection of THR-687. 

The study met its primary end point as there were no dose-limiting toxicity events by day 14 post injection. 

Study shows positive results in treatment of DME with faricimab


Results from exploratory efficacy analyses showed that THR-687 had the potential for rapid onset of action and reasonable durability for improving visual acuity.

“Multiple challenges remain in the management of DME with unmet needs to improve treatment outcomes, speed of treatment benefit, and the duration of response,” said Maturi, a clinical associate professor of ophthalmology at Indiana University School of Medicine, and in private practice at Midwest Eye Institute in Indianapolis, Indiana. “Unlike anti-VEGF agents, integrin antagonists have a broader biologic effect because integrins contribute to the activation of multiple growth factor receptors and are involved in multiple processes resulting in pathological angiogenesis and vascular leakage.”

Maturi noted that based on the phase 1 study findings, a multiple dose, 2-part phase 2 study is planned to select the dose level of THR-687 and to compare it with aflibercept (Eylea, Regeneron) for treatment-naive patients with DME.

Patients were eligible for the phase 1 trial if they had center-involved DME with a central subfield thickness (CST) of 320 µm or greater on spectral-domain optical coherence tomography, best corrected visual acuity (BCVA) between 23 and 62 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and a history of and current response to treatment with anti-VEGF or corticosteroid therapy.

DME strategies directed by knowledge of mechanisms


The study included 3 sequential dose groups: 3 patients received THR-687 0.4 mg, 3 were treated with 1.0 mg, and 6 were treated with 2.5 mg. 

The baseline mean BCVA was 56.3 ETDRS letters for the overall cohort and well-balanced between the 3 dose groups. 

The baseline mean CST was 541.8 µm, and lower in the highest-dose group (499 µm) than in the 2 lower-dose groups (557 µm and 612 µm).

The safety analyses showed a total of 9 adverse events among 5 subjects, but there were no dose-limiting toxicities or serious adverse events.

“All treatment-related adverse events were in the study eye; most were likely related to the injection procedure and the others were likely due to underlying disease progression or concomitant diseases,” Maturi said.

Identifying gaps in anti-VEGF treatment among minorities with DME


Three patients, including 1 treated with the 1.0-mg dose of THR-687 and 2 treated with the 2.5- mg dose, required rescue treatment. Per protocol-defined criteria, this was given for BCVA worsening of 10 ETDRS letters or more, or a 50-µm or greater increase in CST as assessed by the study investigator. 

The BCVA and CST data for these patients were censored at the time of rescue injection and carried forward for the efficacy end point analyses.

Results from BCVA testing showed a rapid onset of improvement, with a mean gain of 3.1 ETDRS letters seen in the overall cohort on the day after injection and a gain of 7.2 letters by day 7. 

A mean improvement of 9.2 letters was seen at month 1, which represented the peak gain, and BCVA remained improved from baseline by a mean of 8.3 letters at month 3.

Post hoc analysis: Protocol V provides more practical DME guidance for clinicians


The change in BCVA appeared to be dose-related.

“The most pronounced improvement in BCVA was observed in the highest-dose group that had a mean improvement of 9.8 letters by day 7, 11.2 letters by day 14, and a mean gain of 12.5 letters at month 3,” Maturi reported.

In the overall cohort, the treatment was associated with a marginal beneficial effect on CST at 7 days and at 1 month with an increase thereafter. However, the highest-dose treatment group had a mean CST decrease of 106 µm at day 14 and maintained a decrease of 36.5 µm at month 3.


Maturi received clinical research funding from Oxurion (previously ThromboGenics) as an investigational study site for the phase 1 clinical trial of THR-687 for DME.

Option has a broader biologic effect for patients.

Cheryl Guttman Krader, BS, Pharm

Articles

Maximizing CXL effectiveness

Research: Treatment targets steroid-induced OHT

DME trial results are positive for intravitreal integrin antagonist

Reducing post-cataract surgery endophthalmitis: Investigators focus on therapeutic regimen