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It is a widely understood concept that the over-prescription of antibiotics has created a selective pressure towards resistant strains, the so-called "superbugs". So the judicious use of antimicrobials has become the standard working principle for most physicians. Yet in spite of our best efforts, resistance continues to be a major problem clinically. It is a story that seems to repeat itself; a new drug hits the market, microbes adapt to environmental pressures, and reports of resistance steadily increase. The same is true of the so-called “fourth generation” fluoroquinolones. The creation of novel fluoroquinolone derivatives with greater safety and efficacy is essential. In fact, for synthetic chemists to create new analogs is relatively simple. But pharmaceutical companies are routinely criticized for not pursuing new solutions to the problem of microbial resistance. The reason may be quite simple: the expense of the drug development process is not trivial. But this trend is beginning to change in response to the necessity of staying ahead of the bugs.
The Ocular TRUST study (and subsequent iterations) was a nationwide antimicrobial susceptibility surveillance system that has shown fluoroquinolones to be the most consistently active against ocular pathogens (Am J Ophthalmol. 2008 Jun;145(6):951-958). Post-operative endophthalmitis cases have until recent years been predominantly atypical Mycobacteria. However, methicillin-resistant Staphylococcus species have since supplanted these concerns in the minds of ophthalmologists. Recent reports suggest that mycobacterial resistance to moxifloxacin may be on the rise (J Cataract Refract Surg. 2007 Nov;33(11):1978-81). Sadly, in cases where resistance is found, the consequences can be tragic. Reports of resistance to earlier generation fluoroquinolones by the various Staphylococcus species are also on the rise. Ciprofloxacin and levofloxacin are seemingly less effective now than in previous years. This leaves moxifloxacin and gatifloxacin as the only effective tools at hand. (J Cataract Refract Surg. 2008 May;34(5):842-5). Reports from 2006 show that acute endophthalmitis in eyes treated prophylactically with gatifloxacin and moxifloxacin arise from Gram-positive organisms that are resistant to even the so-called 4th generation fluoroquinolones, gatifloxacin and moxifloxacin (Am J Ophthalmol. 2006 Nov;142(5):721-5). Currently, moxifloxacin, 0.5% is the main fluoroquinolone in wide use and arguably its days are numbered just like any other antibiotic.
Fluoroquinolones work by targeting the bacterial enzymes DNA gyrase and topoisomerase IV. All fluoroquinolones target both, but may differ in preferred binding site, have different binding affinities, penetration and retention in ocular tissues. This results in varying clinical activity. Fluoroquinolones can be synthesized, and their structure-function relationship characterized. New analogs can be designed to optimize the desired characteristics of broad-spectrum antimicrobial activity, and reduced cytotoxicity to keratocytes, the endothelial layer and epithelium. Efforts to devise better fluoroquinolones for topical ophthalmic use are underway currently. Tactically, this would confer an enormous advantage since a novel fluoroquinolone designed solely for use in the eye would be far less likely to allow for the emergence of resistant strains.
In vitro studies show that fluoroquinolones have an additional somewhat surprising pharmacologic effect that would make them potentially advantageous. They significantly inhibit the production of a host of cytokines in a dose-dependent manner. This would suppress infection-associated tissue inflammation and destruction. (J Antimicrob Chemother. 2008 Jan;61(1):111-6.). This is not without precedent. The immunomodulatory effects of rapamycin are being exploited to inhibit neointimal hyperplasia in coronary angioplasty by coating stents with this potent immunosuppressant.
The fear of complacency in the face of this challenge used to be a major concern among infectious disease epidemiologists and clinicians. Fortunately, effective tools against the ever-increasing microbial resistance problem are being created. At the 2008 AAO meeting, and again at the Hawaiian Eye meeting, researchers presented compelling data on the efficacy of a potentially useful novel fluoroquinolone in the early stages of development (besifloxacin, 0.6%). Attendees of this year's ASCRS meeting had the chance to attend a complimentary CME dinner symposium on this subject. Attendees who were not able to make it to the live event can now participate in an online version of this CME. Click here to get started. This CME event, and the corresponding online CME were jointly sponsored by Medical Education Resources, Inc and Acuity Medical Education.
Some of the topics addressed were:
- emerging trends in the epidemiology of ocular infection
- microbial resistance patterns to fluoroquinolones
- clinical relevance of MDR Staphylococcus strains
- review early stage clinical work comparing new and old fluoroquinolones against bacterial conjunctivitis
The broad spectrum, pharmacokinetics, and pharmacodynamics of novel fluoroquinolone analogs will provide hope that we can remain one step ahead of the microbes.
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