• Cataract/Anterior Segment

    Cataract surgery has become remarkably safe and effective, thanks in part to a general trend toward decreasing postoperative infections. However, retrospective clinical evidence from Minnesota, Missouri, and Utah now indicates a rise in endophthalmitis following clear corneal phacoemulsification.

    Eliminating Endophthalmitis

    Endophthalmitis prophylaxis for cataract surgery is a 2-stage process. The first consists of eradicating infectious agents on the ocular surface and the surrounding tissue so that no organisms can be introduced into the eye during surgery. Although there is no concrete evidence that antibiotics can diffuse into ocular tissues or eradicate pathogens in the eye after topical use, it seems reasonable to consider the second stage of prophylaxis involving the diffusion of antibiotic into the ocular tissues, including the cornea, aqueous humor, and vitreous, to kill any organisms that, despite disinfecting the surface, may have been inoculated during cataract surgery.

    Antibiotic Attributes

    The optimal perioperative antibiotic should have several characteristics. The antibiotic should be bactericidal. An agent that is merely bacteristatic, that does not eradicate bacteria, has no place in perioperative prophylaxis for endophthalmitis. The antibiotic should also have a broad spectrum of activity, especially against gram-positive organisms, because they cause up to 94% of endophthalmitis (as reported by the Charles T. Campbell Ophthalmic Microbiology Laboratory at the University of Pittsburgh).

    In addition, a fast-acting agent is highly desirable so that antibiotic administered prior to surgery will kill all surface bacteria before the start of surgery. An antibiotic with good tissue penetration would also be beneficial. Such an antibiotic, administered after surgery, would be on site within the eye to assist in killing the bacteria introduced during cataract surgery. Finally, a drug with low toxicity is important, especially in this age of topical anesthesia and clear cornea surgery.

    Of the available antibiotics, these criteria currently point directly to the fluoroquinolone family as the single best choice for surgical prophylaxis. Fluoroquinolones are broad-spectrum, fast-acting agents. Aminoglycosides, such as gentamicin, and cell wall antibiotics, such as cephalosporins and vancomycin, are time dependent and therefore, despite high levels of antibiotic, still require anywhere from 8 to 12 hours to kill bacteria.

    In contrast, the fluoroquinolones are concentration dependent, which means at higher doses, they work more quickly. The author's lab has published time kill studies showing the speed with which fluoroquinolones eradicate bacteria (e.g., Pseudomonas spp. in 2 hours). Fluoroquinolones are also of low toxicity and have generally good tissue penetration.

    The difference between the third- and fourth-generation fluoroquinolones is in the mechanism of action. The third-generation fluoroquinolones predominantly bind to either DNA gyrase or topoisomerase IV. This causes lethal breaks in the bacteria chromosome. In the fourth-generation fluoroquinolone, there is a dual mechanism of action, with the fluoroquinolone binding to both DNA gyrase and topoisomerase IV. Although an organism may be resistant to one of these enzymes, it's much more unlikely to be resistant to both.

    Regimen

    Ophthalmic surgeons use a variety of prophylactic methods to keep endophthalmitis at bay. In addition, many widely used methods have entered common practice without strong evidence to support their use.

    The first step for surgical prophylaxis involves clearing the ocular surface of bacteria, which has been shown by multiple studies to be the primary source of the endophthalmitis isolates. This step has 3 parts:

    • Povidone-iodine 5% solution on the skin and in the conjunctival cul-de-sac at least 5 minutes prior to surgery
    • Meticulous lid draping
    • Use of a preoperative antibiotic

    A combination of povidone-iodine and a preoperative antibiotic has been shown to decrease the bacterial flora better then either povidone-iodine or antibiotic alone. The povidone-iodine cleaning step is crucial. In fact, Speaker's paper1 remains the most significant currently available prospective study showing a method of reducing the rate of endophthalmitis.

    While some surgeons begin antibiotic prophylaxis several days in advance to build up drug in the ocular tissue, the author prefers antibiotic prophylaxis starting the day of surgery. A newer generation fluoroquinolone is started 2 hours prior to the operation, given 1 drop every 15 minutes (with a minimum of 4 drops, because that is the therapeutic dose). The author uses no antibiotic during surgery, but at the conclusion of the procedure, a collagen shield soaked in dexamethasone and the antibiotic is placed on the cornea.

    Postoperatively, patients are instructed to use the fluoroquinolone 4 to 6 times a day without stopping or tapering until the epithelial surface has healed, typically no more than 1 week. Obviously, a less toxic agent is preferred postoperatively.

    Rationale

    There are 2 reasons why starting an antibiotic days in advance of surgery may be questionable:

    • The development and selection for resistant strains of bacteria
    • The aim of preoperative antibiotics should be to eradicate the bacteria from the ocular surface.

    A sterile ocular surface means no organisms are available to be introduced into the eye during surgery. Fluoroquinolones act so quickly to eradicate susceptible bacteria that they can be used only hours before surgery with confidence. After surgery, an antibiotic with excellent tissue penetration may provide protection within the ocular tissue against bacteria that may have been introduced during the surgery.

    As far as resistance is concerned, by limiting exposure of the antibiotic pre- and postoperatively, the opportunities for bacteria to develop resistance are minimized. It has been shown that in the majority of cases of endophthalmitis, the causative bacteria were resistant to the antibiotic used prophylactically.

    For the same reason, tapering of antibiotics (ie, subtherapeutic dosing) is ill-advised. In a study by the Proctor Foundation, Hwang and colleagues were able to show that only 2 weeks of twice-a-day dosing of a fluoroquinolone was enough to produce a significant number of resistant isolates. Thus, if the antibiotic isn't present in therapeutic bactericidal concentrations, it shouldn't be present at all. This argues strongly for using short-term, high-dose fluoroquinolones perioperatively. For an anti-infective drug to provide ultimate protection, not only does it have to penetrate well, but it also must not damage the ocular surface.

    Choosing a Fluoroquinolone

    To date, no prospective clinical comparison has been made between fluoroquinolones regarding prevention of endophthalmitis, so we must base decisions on data such as tissue penetration, spectrum of activity, and kill curves. All currently available fluoroquinolones are very effective at killing bacteria, as the author's lab has shown. Gatifloxacin and moxifloxacin have a broad spectrum of activity, are more soluble at physiologic pH, and show excellent penetration into ocular tissues.

    There is emerging evidence that shows that a topical antibiotic could help to reduce the rates of endophthalmitis. The author's lab has published an animal study using a clinical isolate that actually was the cause of a case of endophthalmitis and was then used to reproducibly cause endophthalmitis in rabbit eyes. This study, sponsored by Alcon, first determined that 5 x 104 CFU bacteria injected into the anterior chambers of rabbits' eyes were needed to reliably cause endophthalmitis. Using a total of 40 rabbits in 2 separate experiments, half were treated with saline drops and half with moxifloxacin hydrochloride, 0.5%, 4 times starting an hour before bacterial introduction and 4 times daily after bacterial injection. Masked examinations 24 hours after injection of bacteria found no clinical evidence of endophthalmitis in the topical antibiotic group and a 100% endophthalmitis rate in the saline group.

    The study is the first evidence that prophylactic topical antibiotics alone can prevent endophthalmitis.

    What about Intracameral Anti-infective Therapy for Endophthalmitis Prophylaxis?

    Ophthalmologists have begun to use intracameral antibiotics in conjunction with topical antibiotics to achieve therapeutic anti-infective anterior chamber levels. Although vancomycin is effective against methicillin-resistant staphylococcal infection, it has a very poor killing-curve profile and a narrow spectrum of activity, making it a less desirable agent than a fourth-generation fluoroquinolone such as gatifloxacin or moxifloxacin. Some studies suggest that intracameral vancomycin may actually cause CME. In addition, it has been recommended that vancomycin not be used prophylactically for fear of growing resistance to our last line of defense.

    Recently, a large European collaboration has created earnest discussion among cataract surgeons regarding the future of prophylaxis. The study found a significant reduction in the rates of endophthalmitis when using intracameral cefuroxime at the conclusion of surgery. Although the results are dramatic, and the study may be one of the keys to changing the practice of prophylaxis, honest critiques of the study include:

    • Use of levofloxacin as the topical antibiotic instead of one that acquires higher concentrations while providing more potency
    • Use of efuroxime as the intracameral agent instead of an agent that could have a better pharmaco-kinetic and -dynamic characteristics
    • Relatively high rate of endophthalmitis seen in the study (more than 1 in 400 cases)
    • Potential long- and short-term adverse events, including toxic anterior segment syndrome and anaphylaxis from administering intracameral antibiotics to those allergic to cephalosporins (~10% of the general population)

    Intracameral antibiotics may be the future of cataract surgery endophthalmitis prophylaxis, but important questions must be addressed before they become recommended as the standard of care. Currently, although the author's lab has done some animal studies, the author is not using intracameral antibiotics of any kind for prophylaxis.

    Conclusion


    The prophylactic use of povidone-iodine 5% solution and a perioperative fluoroquinolone antibiotic help to decrease the risk of intraocular infection and are an important part of what makes modern cataract surgery the safe and amazingly successful procedure it has become.

    References

    1. Speaker MG, Menikoff JA. Prophylaxis of endophthalmitis with topical povidone-iodine. Ophthalmology. 1991;98(12):1769-1775.

    2. Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in south Florida and emerging resistence to fluoroquinolones. Ophthalmology. 2000;107(8):1497-1502.

    3. Axer-Siegel R, Stiebel-Kalish H, Rosenblatt I, Strassmann E, Yassur Y, Weinberger D. Cystoid macular edema after cataract surgery with intraocular vancomycin. Ophthalmology. 1999;106(9):1660-1664.

    4. Fukuda H, Kishii R, Takei M, Hosaka M. Contributions of the 8-methoxy group on gatifloxacin to resistance selectivity, target preference, and antibacterial activity against Streptococcus pneumoniae. Antimicrob Agents Chemother. 2001;45(6):1649-1653.

    5. Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistence in bacterial keratitis: a 5-year review. Ophthalmology. 1999;106(7):1313-1318.

    6. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. Gatifloxacin and moxifloxacin: an in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am J Ophthalmol. 2003;136(3):500-505.

    7. Kowalski RP, Karenchak LM, Romanowski EG. Infectious disease: changing antibiotic susceptibility. Ophthalmol Clin N Am. 2003;16(1):1-9.

    8. Mather R, Karenchak LM, Romanowski EG, Kowalski RP. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133(4):463-466.

    9. Barry P, Seal DV, Gettinby, G, et al. ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery: Case for a European multicenter study. J Cataract Refract Surg. 2006;32(3):396-406.

    Author Disclosure

    Dr. Mah states that he has received research support and consultant fees from Alcon Labs, Allergan, and Inspire, Inc.