What treatments may become available to prevent antibiotic resistance in ophthalmology?
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Cationic antimicrobial peptides
Antimicrobial peptides are touted as potential new antibiotics to help treat ocular surface infections. Yet, we have been using these since at least the 1970s.
The combination of bacitracin, polymyxin B and neomycin, often sold as Neosporin, contains two antimicrobial peptides, bacitracin and polymyxin B. It is used as eye drops to treat conjunctivitis, keratitis, keratoconjunctivitis, blepharitis and blepharoconjunctivitis. Unfortunately, some patients develop allergy to the product (most commonly due to neomycin sensitivity), and some bacteria have developed resistance to the components.
The genes for cationic antimicrobial peptides (CAMPs) such as LL-37 and beta-defensins are upregulated during keratitis, and the peptides likely play a part in controlling the infections. However, naturally occurring peptides are inherently susceptible to proteolytic degradation, so synthetic CAMPs have been developed to overcome this problem. Laboratory studies have shown that bacteria find it difficult to become resistant to CAMPs, with few if any cells developing resistance to subinhibitory concentrations after 30 sequential growths. Contrast this to the development of 100-fold resistance to antibiotics such as aminoglycosides and fluoroquinolones under similar conditions.
Several synthetic CAMPs can control keratitis caused by Pseudomonas aeruginosa and Staphylococcus aureus and the fungus Candida albicans in animal models. These CAMPs also synergize with traditional antibiotics such as gatifloxacin, giving both direct antimicrobial action as well as overcoming resistance to gatifloxacin. My laboratory has shown that contact lenses coated with a synthetic CAMP can reduce the incidence of corneal infiltrative events during extended wear.
A search of clinical trials using the database supplied at https://trialsearch.who.int and CAMP names as keywords found that, other than the clinical trials we have performed using the synthetic CAMPs Mel4 or melimine coated onto contact lenses, there have been no other clinical trials of CAMPs for treating or preventing infections of the ocular surface. So, it appears that commercial sources of CAMPs to treat ocular surface infections are still some way off. However, I am hopeful at least one of these will be commercialized given their excellent performance to date in laboratory and animal studies.
Mark Willcox, DSc, PhD, FAAO, FBCLA, FASM, FARVO, is a professor and research director of the School of Optometry and Vision Science at UNSW in Sydney, Australia.
Drug combination
What we currently do in my lab is leverage existing FDA-approved antibiotics and use them in novel ways and new combinations.
This approach has several advantages including superior antimicrobial activity that can potentially overcome antibiotic resistance because antibiotic combinations simultaneously target different processes within the bacterial cell.
One combination that we have been recently developing is polymyxin B/ trimethoprim (PT), which is an existing ophthalmic antibiotic combined with rifampin, an antibacterial agent active against many gram-positive cocci.
We have found this combination to have synergistic antimicrobial activity against both gram-positive and gram-negative bacteria and superior to currently commercially available ophthalmic antibiotics with regards to the speed of killing bacteria and potency against biofilms. But the most compelling results were in our animal studies, where we have shown that PT plus rifampin is able to virtually eradicate both Staphylococcus aureus and Pseudomonas aeruginosa bacterial corneal infections, even when the infecting strain carried multidrug resistance. In these studies, PT plus rifampin outperformed even the gold-standard fluoroquinolones, suggesting that this drug combination may be an important alternative for clinicians to battle circulating antibiotic resistance. We have since gone on to show that PT plus rifampin is effective and synergistic against large panels of clinical ocular bacterial isolates from around the world.
Unfortunately, many pharmaceutical companies have withdrawn from antibiotic development because the return on investment is not as attractive as it is with long-term use drugs. Therefore, a lot of the work on antibiotic discovery is happening in academic labs. Our combination of PT plus rifampin is now ready for early-phase clinical trials in humans, and we expect to start before the end of this year.
Antibiotic resistance is growing, and not many alternative options are currently available. This is an area of much-needed research, and the advantage of our strategy is that we are using approved drugs that already have known safety and efficacy. As such, the regulatory pathway for FDA approval and to the market is much lower. In our lab, we also work on novel antimicrobial drug discovery, but the reality is that by using combinations of existing FDA-approved drugs, we may reach the market, and therefore patients, much sooner and with fewer hurdles.
Rachel A.F. Wozniak, MD, PhD, is an associate professor in the department of ophthalmology at the University of Rochester in New York.
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