Seeking the holy grail treatment for endophthalmitis

The latest treatment option for endophthalmitis offers versatility and plasticity, is programmable for individualized drug delivery, and is 100% biodegradable. 

This article was reviewed by Irmgard Behlau, MD

Various approaches have been developed to treat endophthalmitis, including topical and systemic drugs and periocular and intravitreal injections. The noninvasive methods of topical and systemic means of delivery are the goals because of their lack of invasiveness.

With injections, there is always the risk of development of endophthalmitis. However, nothing is perfect and the holy grail remains elusive, according to Irmgard Behlau, MD.

According to Dr. Behlau, research assistant professor, Tufts University School of Medicine, Tufts Medical Center, Boston, drops work if the patient has kerato­endophthalmitis, but successful delivery is limited to only 1% to 7% of the drug. Frequent instillation every one to two hours is mandatory, and the drug has to get through the natural barriers of the ocular surface and tears.

Related: Diagnostic advances offer glimpse of endophthalmitis pathogens 

Recent advances that have been achieved are antibiotics with small molecular weights, increased residence times and permeability, decreased toxicity, and slower degradation rates.

Dr. Behlau and colleague Joseph Ciolino, MD, explored an antibacterial-eluting contact lens that contained ciprofloxacin in one model and econazole in another model, both of which are small-molecule drugs. 

The ciprofloxacin-containing contact lens was a zero-order delivery system, and the econazole-containing lens demonstrated efficacy in the delivery of that antifungal drug.

One drawback to this is that producing such a treatment modality is burdensome and the question regarding how efficiently the drugs hit their targets remains unanswered, she explained.

Related: Study targets therapies for endophthlamitis 

A mucoadhesive contact lens, developed by Prashad Garg, MD, was formulated from polyethylene glycol, glycerol, chitosan, and glacial acetic acid that contains moxifloxacin 0.4% and dexamethasone 0.1%. With a small burst, this contact lens achieved zero-order kinetics. 

A rabbit keratitis study showed that the moxifloxacin concentrations to the lens and cornea were high, but those in the aqueous and vitreous were wanting. 

“This result supports the notion that topical antibiotics do not work because they cannot penetrate to where they need to be. The concept of using them is not beneficial. The contact lenses provide better penetration, but the complexity and cost increase and the small molecules are limited,” Dr. Behlau stated.

Other approaches, including subconjunctivally, intracamerally, and transsclerally, are reliably unreliable.

Related: Small changes can help beat the endophthalmitis bug 

Systemic delivery
In light of these short falls, all roads always seem to lead back to systemic administration, Dr. Behlau said, but it comes with a boatload of disadvantages. 

Providing access to drugs through the retinal pigment epithelium, Dr. Behlau explained, is confounded by the efflux pumps, P-glycans, and the multidrug resistant associated proteins. The back of the eye is inaccessible to systemically administered drugs. 

“The rule of thumb is that if the data show that a new drug can penetrate into the central nervous system, the drug often can penetrate into the eye; however, in order to access the eye, higher doses are needed and often intravenous administration.

The fluoroquinolones and linezolid can reach the eye when administered systemically, the latter of which may be useful for methicillin-resistant Staphylococcus aureus. Systemically administered antifungals are also useful for penetrating the eye.

Related: Postop endophthalmitis rates similiar despite dissimilar practice patterns 
 

Intravitreal access
Issues with this route of delivery are the sizes of the molecules injected and the elimination times. The route of elimination-anteriorly or posteriorly-affects the ocular retention time, with drugs eliminated anteriorly are retained longer. 

“The fluoroquinolones, for example, clear the eye posteriorly, which is why the drug has to be administered so frequently,” Dr. Behlau pointed out. 

It is also noteworthy that inflammation and pars plana vitrectomy increase the rate of elimination. For example, ciprofloxacin injected intravitreally remains in the eye for about 60 hours in an uninfected eye. In the presence of an infection, the drug is eliminated in about 16 hours.
 

Related: Are intracameral antibiotics the answer for endophthlamitis?

Drug-device combinations
There has been an explosion in the use of these drug delivery system, as evidenced by the drug-eluting contact lenses and intracameral implants, and in devices to treat age-related macular degeneration and diabetic retinopathy with direct delivery into the posterior segment, she explained.

According to Dr. Behlau, drug device combinations in many cases overcome the ocular barriers and elimination mechanisms.

“Anterior segment systems enhance the precorneal retention and tissue permeation,” she explained. “Posterior segment devices require sustained drug release to minimize the injection frequency.” 

Dr. Behlau pointed out that these devices are invasive and importantly carry the risk of foreign body infection.

Related: Diagnostic advances offers glimpse of endophthalmitis pathogens 

An antimicrobial device implant is the first of its kind that can overcome some shortcomings of these drug devices is the antimicrobial silk ocular drug delivery implant that was designed by Dr. Behlau, Chiara Ghezzi, PhD, and David Kaplan, PhD , Biomedical Engineering at Tufts University, Boston, MA, for treating chronic posterior segment diseases. 

This implant is coated with N,N-hexy, methyl polyethylenimine to prevent infection, be biocompatible, and enable the zero-order sustained delivery of larger molecules, Dr. Behlau explained. 

This 4-mm to 5-mm device, with an inner diameter than can accommodate a 27-gauge needle, can be implanted without creating an incision. It also can retained in the eye in the pars plana as a result of its peanut shape. This device can stay in the eye for eight months without the need for an antibiotic.

“My hope is that this type of implant can be used to treat endophthalmitis over a long period of time and other diseases,” Dr. Behlau concluded. “This device has versatility and plasticity, it is programmable for individualized drug delivery and it is 100% biodegradable.” 

Read more by Lynda Charters

Irmgard Behlau, MD
E: irmgard.behlau@tuftts.edu
Dr. Behlau has no financial interest in any aspect of this report.