BEYOND ANTIBIOTICS

Severe keratitis on day four after LASIK surgery in a healthcare worker due to culture proven methicillen-resistant Staphycococcus aureus (MRSA). Image courtesy of Terence P O'Brien MD

The growing threat of antimicrobial resistance will require new ways of looking at treating infection, Terrence P O’Brien MD warned the 7th International Congress on Ocular Infections in Barcelona, Spain. “We are falling woefully behind in the war between microbe and man, which means we need to continue learning more about microbes,” said Dr O’Brien, Professor of Ophthalmology, Charlotte Breyer Rodgers Distinguished Chair, Bascom Palmer Eye Institute, Palm Beach, Florida, USA.

Dr O’Brien described our current approach to infection as a so-called “Exorcist” approach, in which we try to saturate the eye with high antibiotic concentrations at frequent intervals in order to rid the eye of “evil” microbes.

“Yet this is not ideal, as humans are colonised by germs, and symbiosis is more important than asepsis. A better understanding of the pathophysiology of infections might allow us to develop more nuanced treatment, from rapid, reliable diagnostic methods to new treatments with novel targets and specialised delivery modalities,” he said.

This is an interesting development, considering a quotation from 1960 by then American Surgeon General, the government’s top physician: “It is time to close the book on infections diseases and declare the war against pestilence won.”

Not exactly! Those were exciting times, when new antibiotics were continuously being developed and S aureus had not yet acquired methicillin resistance.

MAGIC BULLET

“The ideal antimicrobial, the perfect ‘magic bullet’ would demonstrate a broad spectrum of activity, good tolerance, low toxicity, microbicidal efficacy, rapid kill, good penetration and coverage of emerging resistant organisms,” said Dr O’Brien.

Dr O’Brien further discussed new treatment delivery technologies such as smart polymers, intraocular inserts, iontophoresis and intravitreal gene therapy, before placing the emphasis back on antimicrobial resistance.

“Bacterial isolates from ocular infections have been showing increasing resistance to fluoroquinolones. In the early 1990s, cultures from keratitis, conjunctivitis and endophthalmitis cultures demonstrated organisms that were nearly 100 per cent susceptible to this class of antibiotics, but by the early 2000s this had dropped by nearly 50 per cent for keratitis and conjunctivitis, and by nearly 100 per cent for endophthalmitis. Similar trends exist regarding coagulase-negative staphylococcal endophthalmitis.”

Other options must be found, he stressed, starting with naturally occurring antibacterial agents already present in our bodies. These include hypochlorous acid, antimicrobial peptides and defensins.

Hypochlorous acid (HOCL), which is released from neutrophils as part of the body’s immune response, kills microorganisms and helps suppress the body’s inflammatory response.

“Hypochlorous acid 0.01 per cent has excellent activity against a broad range of pathogens, including those commonly found on the eyelids and lashes. And it’s one thousand times less toxic then Betadine®,” he noted.

Antimicrobial peptides, such as lactoferrin, dermcidin and the defensins, take advantage of basic differences between prokaryotic and eukaryotic cells, such as their electric charge, that allow for targeted cidal activity. They are present in everything from amoebas to humans, and in vertebrates are particularly abundant in external mucosa, immune cells and the intestinal tract.

ANTIMICROBIAL PEPTIDES

Present in keratocytes, antimicrobial peptides permeabilise cell membranes and can destroy cell walls. They also stimulate both innate and adaptive immune responses, cause autolytic enzyme release and block cell envelop synthesis. But can they be developed as new clinical antibiotics active against eye infections?

“Manufacturing these peptides is currently very expensive, although organic mimics or modular design may help. It may also be possible to produce in bacteria or plants, although degradation by proteases might remain a problem,” said Dr O’Brien.

One investigational agent, peptide antibiotic MX-226, has been shown to significantly limit catheter colonisation in phase IIIa clinical trials.

An alternative is brilacidin, a polymer-based antibiotic currently in human clinical trials. Brilacidin is a small, defensin-mimetic compound modelled after host proteins that is easy to synthesise from commercial agents. It has demonstrated activity against MRSA, MRSE and VRE, he reported.

Brilacidin, with its long tissue half-life, has a rapid bactericidal effect that minimises the possibility of bacterial mutations and thus resistance. It is currently being developed by Cellceutix for ophthalmic indication.

“Not all of the structural characteristics of what makes a good peptide antibiotic are known at this time, so more research is needed to move development forward,” he concluded.

Terrence P O’Brien: tobrien@med.miami.edu