Expert explains latest advances in ophthalmic antibiotics

John A. Hovanesian, MD, FACS, interviews Francis S. Mah, MD, about resistant organisms, new antibiotics and treatment strategies.

John A. Hovanesian

John A. Hovanesian, MD, FACS: Today we are joined by Francis S. Mah, MD, an assistant professor of ophthalmology at the University of Pittsburgh and the director of the Campbell Ophthalmic Microbiology Laboratory. Dr. Mah, thanks for joining us.

Francis S. Mah, MD: Thank you very much for the invitation.

Dr. Hovanesian: Tell us about the importance of new antibiotics that are available on the market today for ophthalmologists.

Dr. Mah: I think it is important to expand the armamentarium that we ophthalmologists have in battling infections. I think that there are several stimuli that bring to light the need for new anti-infectives. One is that there are new pathogens. Fusarium is not new, but there was a huge influx of Fusarium from contact lenses. Acanthamoeba is on the rise. And then there are different pathogens such as Mycobacterium that also cry out for a need for new anti-infectives.

I think the other stimulus and motivating factor for new anti-infectives is pathogen resistance. Resistance always develops, and because of resistance, what we had previously been using is no longer effective, which requires the need to readdress anti-infectives.

Dr. Hovanesian: We already have some good antibiotics that are in common use. Are there already resistant organisms becoming prevalent?

Francis S. Mah

Dr. Mah: Yes. Right now, especially in the United States, and probably worldwide, fluoroquinolones are a broadly used and popular class of antibiotics. The last generation, the 8-methoxy fluoroquinolones, such as moxifloxacin (Vigamox, Alcon) and gatifloxacin (Zymar, Allergan), were released approximately 3 or 4 years ago, and we are seeing some development of resistance to moxifloxacin and gatifloxacin. And one of the biggest newsmakers is methicillin-resistant Staphylococcus aureus, or MRSA. There is increasing evidence in the peer-reviewed literature, as well as from our own laboratory, that there is an increase in MRSA. At our laboratory, we are showing that approximately 35% of our Staph aureus isolates in endophthalmitis and keratitis are MRSA, and among those isolates, approximately 60% are susceptible, which means that approximately 40% are resistant as measured by systemic means, which are not a true indication of resistance in the eye; however, it is the only benchmark that we have.

Dr. Hovanesian: And there were a high proportion in an ASCRS study of postoperative LASIK infections, 28% that were MRSA. What does this say for our future treatment of routine corneal surgery?

Dr. Mah: That study, which was done by the ASCRS Corneal Clinical Committee, which I am a member of, was alarming because the changing trend in terms of the infections is bringing to light the pathogens that are involved in ocular infections.

In 2001, when the initial survey was done, it showed that Mycobacterium were approximately 50% of the pathogens if there was an infection after LASIK surgery. That was reduced all the way down to less than 5% in 2004, primarily due to moxifloxacin and gatifloxacin use prophylactically after surgery, improved education and better surgical technique And in 2004, the survey showed that Staph aureus had become the overwhelming majority of cases. The researchers did not differentiate between methicillin-resistant or methicillin-susceptible Staph aureus; however, greater than 50% of the isolates causing post-LASIK infections were Staph aureus. In this newest survey, Staph aureus was again the No. 1 cause of infections; however, they did differentiate this time, and we found that 28% of the isolates were MRSA by themselves, and so I think what this brings to light is the fact that we need to be a little bit more concerned about what may be causing infections.

Dr. Hovanesian: There are two new antibiotics available to ophthalmologists in eye drop form, azithromycin (AzaSite, Inspire Pharmaceuticals) and levofloxacin (Iquix, Vistakon). Where do these fit into clinical practice for a comprehensive ophthalmologist?

Dr. Mah: Levofloxacin 1.5% is a reformulation of a product that we know as levofloxacin 0.5%. The increased concentrations potentially do two things. One is they increase concentrations into the tissues, which we know is where the infection is being caused — not only the corneal tissue, but also the anterior chamber concentrations. There are some initial animal studies, as well as a study that Edward J. Holland, MD, did in penetrating keratoplasty patients, showing that there are extremely high levels of levofloxacin getting into the cornea as well as the anterior chamber.

The other thing that potentially would happen with the higher concentrations is that you could potentially overcome some amount of resistance due to the fact that you are getting high levels into the tissues. The other reformulation that was made was to remove the preservative, benzalkonium chloride, so this is now our second anti-infective without a traditional preservative. In other words, it is self-preserved, and that trend may become more popular, at least in terms of anti-infectives in the United States.

This drug is approved for the treatment of bacterial keratitis, and so this is another difference because moxifloxacin and gatifloxacin are not approved for corneal ulcer treatment. So this would actually be an on-label use for levofloxacin 1.5%.

As far as azithromycin 1%, that is a drug that I think most ophthalmologists are well-aware of. Many physicians have probably prescribed it or have taken it themselves since it was released in 1992. It is a very active molecule; however, it is primarily bacterostatic in nature. It has a relatively broad spectrum of activity, covering many of the pathogens involved in bacterial conjunctivitis, and basically it is being found out to be gentle to the eye. In fact, there are some studies that indicate that there may be some anti-inflammatory components. Obviously, the effect of that and the impact of that on the eye still remain to be tested and seen.

Azithromycin is in a vehicle that is rather viscous. It is called DuraSite (InSite Vision), and the DuraSite actually does two things. It increases the contact time so that you are getting potentially higher concentrations into the tissues. And it actually allows for azithromycin to be compounded in a liquid form. Without the DuraSite, the azithromycin would not be able to be in a solution or suspension.

Azithromycin has a unique quality in that it achieves extremely high concentrations in tissues. That is something that has been well-known and well-documented in the systemic world, and we are finding the same properties in the eye. One of the unique properties in terms of management of infections with azithromycin is it has excellent activity against atypical Mycobacterium and atypical bacteria, such as Mycoplasma and Legionella, so this is obviously a nice addition to our armamentarium to have a commercially available product that can cover mycobacteria.

The actual product is approved for bacterial conjunctivitis. Another nice feature of the high tissue concentrations is the fact that the dosing is only nine drops. The entire treatment, you have two drops the first day, two drops the second day and then one drop the following five days, which adds up to nine drops. And so for pediatrics, for example, where we all know that it is difficult getting drops into children, this may be beneficial.

Dr. Hovanesian: What about the role of azithromycin in treating anterior and posterior blepharitis? Do the tissue levels achieve high enough concentration to make a difference for longer-term use?

Dr. Mah: That is an interesting question. I think that is primarily where many ophthalmologists are adopting the use of azithromycin. We all know about erythromycin and how widely spread the use of erythromycin is for blepharitis, whether anterior or posterior, and azithromycin obviously would seem to be a natural fit because it is in a similar class, the macrolide class, and therefore has a similar spectrum.

There have been some initial studies in human conjunctiva and eyelids. There are some rabbit eyelid studies, and they show there are some extremely high concentrations in the eyelid tissues, and so you would imagine that this would be an advantage in terms of the treatment of posterior blepharitis specifically. Regarding anterior blepharitis, typically that is an infectious process, so obviously an antibiotic would be beneficial for it. And I think including hyperthermia or warm compresses, as well as eyelid scrubs or massage, is a nice addition to the treatment for blepharitis.

Dr. Hovanesian: Is it likely that in the near future we will be able to use a twice-daily frequency antibiotic after routine surgery such as cataract surgery?

Dr. Mah: Yes, potentially we will be able to. In the development of these anti-infectives, not only are manufacturers trying to make them more potent, as well as increase their spectrum of coverage, they are also trying to increase their pharmacokinetic profile so that the dosing can be reduced. And we know that, for example, moxifloxacin and gatifloxacin, when they are used systemically, they are once-a-day medications, so the pharmacokinetic profile is improved. Obviously, with a once-a-day drop or a twice-a-day drop, you have much better compliance compared with a three- or a four-times-a-day medication. So I do think that decreasing frequency of medications is another trend that we are seeing in ophthalmology and will probably extend to the anti-infectives as well.

Dr. Hovanesian: Is there a single take-home message that you can give us for the comprehensive ophthalmologist for how the new antibiotics that are available might change our clinical practice in the future?

Dr. Mah: I think they are nice additions to our armamentarium. I think it remains to be seen how they are going to be incorporated to what we use for ocular infections. Obviously, the difference in terms of the spectrum of coverage for azithromycin is nice with the addition of Mycobacterium and some of the other atypical bacteria. For azithromycin and levofloxacin 1.5%, the increased concentrations could be nice characteristics. Finally, having an on-label drug for corneal ulcers is a nice addition.

Dr. Hovanesian: Dr. Mah, thanks very much for joining us.

For more information:

• John A. Hovanesian, MD, FACS, is a clinical instructor at the UCLA Jules Stein Eye Institute and is in private practice in Laguna Hills, Calif. He can be reached at Harvard Eye Associates, 24401 Calle De La Louisa, Suite 300, Laguna Hills, CA 92653; 949-951-2020; fax: 949-380-7856; e-mail: drhovanesian@harvardeye.com. Dr. Hovanesian is a consultant for Allergan, Bausch & Lomb, Inspire, Ista, and Sirion Therapeutics.
• Francis S. Mah, MD, can be reached at University of Pittsburgh Medical Center, Eye and Ear Institute, 203 Lothrop St., 8th Floor, Pittsburgh, PA 15213; 412-647-2200; fax: 412-647-5119; e-mail: mahfs@upmc.edu. Dr. Mah does research and is a consultant for Alcon, Allergan, InSite, Inspire and Vistakon.

Reference:

• Donnenfeld ED, Kim T, et al.; American Society of Cataract and Refractive Surgery Cornea Clinical Committee. ASCRS White Paper: Management of infectious keratitis following laser in situ keratomileusis. J Cataract Refract Surg. 2005;31(10):2008-2011.