Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

•Non-specific treatment typically follows a step-ladder approach, beginning with topical and periocular corticosteroid therapy, through oral corticosteroids, disease modifying agents and immunosuppressants

•Use of oral corticosteroid therapy is generally efficacious, but must be limited in time and dosage to avoid severe complications associated with chronic corticosteroid use

•Intraocular corticosteroids may be used for severe disease. These may be given by direct injection, or placement of a sustained release device (such as the fluocinolone acetonide implant)

•Disease modifying agents in use for uveitis include methotrexate, azathioprine, cyclosporine A, tacrolimus, and mycophenolate

•Biologic agents used for uveitis include the tumor necrosis inhibitor infliximab, and the T-cell receptor antagonist daclizumab

•Alylator immunosuppressants used in the treatment of uveitis include cyclophosphamide and chlorambucil.

VII. EYE ON NEW DISCOVERIES

BOX 13.1

•Certain forms of anterior segment uveitis have recently been associated with chronic infection. This includes Fuchs’ heterochromic cyclitis, which is now thought to be due to rubella infection, and a form of chronic anterior uveitis with elevated pressure due to cytomegalovirus infection. Investigations are under way for forms of posterior uveitis to determine if specific infections may underlie certain forms.

•Intraocular drug delivery systems are evolving rapidly. These include administration of specific biologic agents such as

monoclonal antibodies by direct injection into the eye, controlled release devices (such as in the fluocinolone acetonide (Retisert®) implant), and novel “bioreactor” technologies to produce soluble proteins in the eye.

•Biologic agents such as infliximab and daclizumab have remarkable efficacy for treatment of certain forms of posterior uveitis. At least a dozen novel biologics are in late stage clinical trials in rheumatology. These may have high utility in the treatment of uveitis as well.

•A direct comparison of intraocular corticosteroid (the fluocinolone acetonide implant) and traditional systemic medical therapy – the Multicenter Uveitis Steroid Trial (MUST) – is presently under way and will yield important insights into outcomes of uveitis patients treated with both modalities.

VIII. REFERENCES AND FURTHER

READING

Boyd, S.R., Young, S., Lightman, S. (2001). Immunopathology of the noninfectious posterior and intermediate uveitides. Surv. Ophthalmol. 46(3), 209–233.

Galor, A., Perez, V.L., Hammel, J.P., Lowder, C.Y. (2006). Differential effectiveness of etanercept and infliximab in the treatment of ocular inflammation.

Ophthalmology 113(12), 2317–2323.

Holland, G.N. (2004). Ocular toxoplasmosis: a global reassessment. Part II: disease manifestations and management. Am. J. Ophthalmol. 137(1), 1–17.

Jabs, D.A., Nussenblatt, R.B., Rosenbaum, J.T. (2005). Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am. J. Ophthalmol. 140(3), 509–516.

Jabs, D.A., Rosenbaum, J.T., Foster, C.S., Holland, G.N., Jaffe, G.J., Louie, J.S., Nussenblatt, R.B., Stiehm, E.R., Tessler, H., Van Gelder, R.N., Whitcup, S.M., Yocum, D. (2000). Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am. J. Ophthalmol. 130(4), 492–513.

Jaffe, G.J., Martin, D., Callanan, D., Pearson, P.A., Levy, B., Comstock, T., and the Fluocinolone Acetonide Uveitis Study Group. (2006). Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology 113(6), 1020–1027.

Lim, L., Suhler, E.B., Smith, J.R. (2006). Biologic therapies for inflammatory eye disease. Clin. Experiment. Ophthalmol. 34(4), 365–374.

Martin, D.F., Sierra-Madero, J., Walmsley, S., Wolitz, R.A., Macey, K., Georgiou, P., Robinson, C.A., Stempien, M.J., and the Valganciclovir Study Group (2002). A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N. Engl. J. Med. 11;346(15), 1119–1126. Erratum in: N. Engl. J. Med.

12;347(11), 862.

I. INTRODUCTION

The eye is amazing. It is open to the environment, but rarely gets infected. Nevertheless, when it does become infected, gram-positive bacteria, like Staphylococcus aureus, are the usual cause. Fungi and viruses are also culprits, but infections by these organisms occur less frequently. Anti-infective agents, like aminoglycosides, fluoroquinolones, tetracyclines, and macrolides, have been useful in treating ocular infections, but microbial resistance to these agents has challenged the pharmaceutical research community to create better and more effective anti-infective agents for prophylaxis and therapy. Classical antibiotic families and approaches still have merit, and families like the fluoroquinolones still offer some fruitful candidates. Although antibiotic research is drying up in Big Pharma companies, other smaller companies are taking up the gauntlet and creating novel ways to handle these ocular pathogens. This chapter reviews the approaches taken and some of the more recent new entities that might prove useful for preventing or treating ophthalmic infections.

II. THE OCULAR ASSAULT

Although the eye rarely gets infected, the ocular environment is warm, moist, and rich in proteins and sugars, and offers a good opportunity for invasion by microorganisms. Microorganisms can enter the eye through ocular injury, trauma, through contact lens use, or even during surgery. Successful invasions yield bacterial, viral, fungal or protozoan infections of the eye (e.g. conjunctivitis, blepharitis, keratitis, endophthalmitis).

III. THE ENEMY

Microorganisms have been terrorizing humankind for generations. Our eyes are not

immune to these assaults. It is probable that Moses of the Book of Genesis (Figure 14.1) suffered with bacterial conjunctivitis or keratitis during his wanderings in the desert. He was surrounded by sandy irritants and microbial opportunists like Staphylococcus aureus (Figure 14.2). The types of organisms invading his eyes haven’t changed much over the years. Microbial taxonomists since Carl Linnaeus (1707–1778) have named and renamed organisms based on the technology of the times and what they knew about their physical, nutritional, and pathogenic characteristics. Today, the genetic makeup of microorganisms is the primary basis for nomenclature and microbial taxonomy. The list of potential microbial enemies is long: there are over 4400 published and approved bacterial species, over 100,000 species of fungi, over 12 genera of protozoa that infect the human body, and over 80 virus families representing over 270 genera of viruses. Nevertheless, we are lucky – the array of microorganisms successfully infecting the eyes is limited and finite (Table 14.1). Currently, there are only antibacterials, antifungals, antiprotozoans or antivirals, and no topical “broadest possible spectrum” antimicrobials for therapy against bacteria, fungi, protozoa, and viruses. Gram-positive bacteria still predominate as the most common enemy of our eyes today (Table 14.2).

IV. AVOIDING OCULAR

INFECTIONS

The strategy is fairly simple – keep microorganisms out of and away from the tissues of the eye. Preventing infection involves the concept of prophylaxis (from the Greek meaning “to guard against beforehand”) that involves keeping the eyes clean and free of microbes by good hygiene, disinfection, antisepsis or antibiotic treatment. If this approach is not successful and infection occurs, then the strategy is refocused on killing or eliminating the offending microbe through therapeutic

means, i.e. treating the eye with antibiotics or antimicrobial products.

V. EVOLUTION OF

ANTI-INFECTIVE AGENTS

The treatment of ocular infections over the centuries has ranged from hot and cold packs, ocular massages and eye washes

with stream water, frankincense gum, and boric acid solutions, mixtures of tortoise brain and honey, freshly disemboweled frog mixed with raw onion, plant extracts and minerals, milk, wine, oils, mercuric salts and acupuncture (Astbury, 2001). Sulfas and antibiotics became available in the 1930s and 1940s, and opened up the golden age of antibiotics. Ophthalmic antibiotics available from the 1950s to 1980s were effective,

but sometimes toxic, limited in spectrum, and usually bacteriostatic. Today, these have been replaced by significantly broader spectrum, more effective and safer therapies. In general, eye care practitioners no longer use sulfonamides, chloramphenicol, polymyxin, or bacitracin to treat ophthalmic infections. Aminoglycosides (e.g. neomycin, gentamicin, tobramycin) had their heyday, but their use is waning as better agents, like the fluoroquinolones, have become available and preferred.

VI. PHARMACEUTICAL

RESEARCH

The grandparents of most of today’s antibiotics were agents discovered in the 1940s and 1950s, that interfered with the synthesis of the bacteria’s cell wall, its protein or its DNA, so that they could not reproduce themselves. The molecular structures of earlier antibiotics were tweaked to keep them working against resistant bacteria, but new approaches and families are constantly needed.

A. Big Pharma vs. Small Biotech

Some major pharmaceutical companies have discontinued antibiotic drug research and focused on chronic diseases, like Alzheimer’s, cancer, or cardiovascular diseases, because of cost of development and the rapid development of antibiotic resistance. Even though the worldwide anti-infective market is the second largest pharmaceutical market, with sales equal to $25 billion in 2005, there have been few new antibiotic launches or new antibiotic classes. Anti-infectives usually provide short-term treatment, so there are no “patients for life”. Infections are becoming increasingly resistant to existing antimicrobial agents (perhaps most alarming) and the pharmaceutical pipeline of new antimicrobials, particularly antibacterial drugs, is drying up (Livermore, 2004;

Bosso, 2005). Smaller biotech firms have taken up the R&D challenge. Nevertheless, Big Pharma is now being enticed back into anti-infective research and development business because of the lack of candidates that overcome resistance. The recent launch of a glycylcycline, Wyeth’s tigecycline, represents one of the first new antibiotic classes to be introduced in years. The need for effective antimicrobial products for ophthalmic use continues as the ocular antimicrobial market continues to grow and expand. The worldwide ocular antiinfective market in 2005 was over US$900 million. Considering the threat of bioterrorism, much research has been focused on targets like smallpox, anthrax, plague, botulism,tularemia,viralhemorrhagicfevers (i.e. Ebola, Lassa, Arena viruses) – infections that present greater morbidity than ocular infections. While the Big Pharma companies are funneling their research funds into anti-hypertensive, arthritis, sexual dysfunction, Alzheimer’s or diabetes research, companies dedicated to ophthalmic research, like Alcon, plus a few “Small Pharma” or start-up biotech companies focusing on a limited number of antimicrobial candidates or “one-trick ponies” will be the future source of antimicrobials for ophthalmology.

B. Japanese Antibiotics

Japan was the third country, after the US and the UK, to become self-sufficient in penicillin manufacture, as early as 1948. Besides the production of penicillin, much effort was made nationwide in exploratory research on anti-infective products. One of my professors at the University of Texas at Austin, Jackson W. Foster, was acclaimed as the “father of Japanese antibiotics” during the 1940s–1950s through his participation in the post-war development of this industry. There are currently over 100 useful antibiotics and related agents of Japanese origin, and over 40 have been licensed around the world. The first antibiotic from Japan was colistin (discovered in 1950), followed

by well-known agents such as kanamycin (1957), cefazolin (1969), amikacin (1972), piperacillin (1976), norfloxacin (1977), cefoperazone (1978), ofloxacin (1980), clarithromycin (1984), and meropenem (1987). The major groups include the beta-lactam and fluoroquinolone antibiotics. In Japan, fluoroquinolones are the most widely prescribed antibiotics in ophthalmic solutions and all are benzalkonium chloride-free products.

VII. OCULAR ANTI-INFECTIVE

RESEARCH

Whether a company is developing an antibiotic for systemic or ophthalmic usage, the process is similar and involves an in vitro screening step, an in vivo infection step and finally clinical trials. Many ophthalmic antibiotics today were first assessed for treating systemic or non-ophthalmic infections. The future challenges for ophthalmic anti-infective research are daunting. Every new product must have its unique uses and advantages over the existing products.

We demand more and more from our topical antibiotic products for ophthalmology (Table 14.3).

VIII. THE SCOURGE OF

ANTIBIOTIC RESISTANCE

Antibiotic resistance developed quickly in the past, starting with resistance to sulfonamides in the 1930s and to penicillin, streptomycin, tetracycline and erythromycin in the 1940s and 1950s. In the 1960s, microbes developed resistance to nalidixic acid, the great-grandmother of the fluoroquinolones. Significant resistance to vancomycin developed in the 1970s, and to the early fluoroquinolones (i.e. norfloxacin) in the 1980s. These events have focused on more potent agents effective against resistant strains of bacteria. Fluoroquinolones have become the dominant family of ophthalmic antibiotics. But even the older fluoroquinolones (e.g. ofloxacin, ciprofloxacin) have lost much of their effectiveness against some important ocular isolates. Considering

all of the characteristics for an ideal ophthalmic antibiotic product, moxifloxacin ophthalmic solution 0.5% represents one of the best antibiotic products of choice for treating and preventing ophthalmic infections today (Schlech and Blondeau, 2005). Growing microbial resistance to current antibacterial agents, and widening gaps in antibiotic coverage create a need for more potent and genetically smart fluoroquinolones. When the first ocular fluoroquinolone, ciprofloxacin, became available for treating bacterial conjunctivitis and keratitis roughly a decade and a half ago, there was tremendous excitement. This product was also used to prevent and treat ocular bacterial infections, especially before, during, and after cataract and refractive surgery. Today, however, this most impressive weapon has lost some of its punch (Goldstein et al., 1999; Hwang, 2004; Thompson, 1999). Several groups of microorganisms have developed resistance to ciprofloxacin and its sister fluoroquinolones, ofloxacin and levofloxacin, more quickly than imagined, and the levels of resistance are increasing each year (Alfonso, 2003). The bacteria hold most of the cards for the future. They will evolve and respond to their environment, and produce progeny that will be resistant to today’s antibiotics. Humans can only try to keep ahead of these clever creatures. Abandoning the old antibiotics and creating new entities are the only ways to keep up with these resistant trends. Continuing to use older, previous-generation antibiotics will only facilitate the continued development of resistant strains (Dahlhoff and Schmitz, 2003). Although investigations are ongoing, to the author’s knowledge there is no substantial study that proves that any topical ocular application of antibiotics induces microbial antibiotic resistance distal to the site of instillation. Conjunctivitis occurs worldwide and affects people of all ages, all social strata, and both sexes. It has been cited as one of the most frequent causes of self-referral in the practice of

comprehensive ophthalmology (Chou et al., 2004). According to the American Academy of Ophthalmology (AAO, 2003) “conjunctivitis infrequently causes permanent visual loss or structural damage, but the economic impact of the disease in terms of lost work time, although undocumented, is doubtless considerable”. The annual worldwide sales of anti-MRSA agents are projected to be in excess of $2 billion in 2007. The prevalence of MRSA in hospitals and communities is about 64–68% (Kowalski et al., 2003; Armstrong, 2000). Gaynor et al. (2005) have reported that the topical use of 1% ophthalmic tetracycline ointment may increase the antibiotic resistance of Streptococcus pneumoniae in the nasopharynx.

IX. THE ATTACK STRATEGIES – ANTIMICROBIAL TARGETS

Unlike glaucoma, cataracts, or AMD, infectious diseases involve the host being attacked by another organism, the pathogen. Strategies for therapy focus on the unique differences between the microorganism, its metabolism and its pathogenic process, and those of the host. An ideal or successful target is one that involves a process unique to the pathogen, but not found in the human host. The following are the major targets:

•Interfering with protein synthesis – e.g. aminoglycosides, sulfonamides, tetracyclines, macrolides, chloramphenicol, clindamycin, clotrimazole, erythromycin, rifampicin, rifamycins, ansamycins, oxazolidinones, pleuromutilin, lincosamides, proteases, specific inhibitors of 23S, 30S and

50S ribosomal subunits, muramoyl pentapeptide carboxypeptidase, polypeptide deformylase (PDF), methionyl-tRNA synthetase, matrix metalloproteinase, glutamate racemase, metallo-enzyme/metalloprotease.

•Interfering with DNA and RNA synthesis – e.g. fluoroquinolones,