ByEric D. Donnenfeld, MD

July 01, 2007

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What is the best intracameral agent?

ByEric D. Donnenfeld, MD

In recent years, medical professionals have placed increased emphasis on the importance of evidenced-based medicine in clinical decision-making. Ophthalmologists who want to base their regimen for endophthalmitis prophylaxis on clinical trials of particular prophylactic techniques that demonstrate an evidence-based reduction in post-cataract surgery endophthalmitis find few published studies to guide them.

Available literature

In 1974, Allen and coworkers at Massachusetts Eye and Ear Infirmary showed that topical antibiotics reduced the incidence of endophthalmitis by 92% in 36,000 consecutive cataract surgeries.¹ Although some may question whether data from 1974 can be applied in 2007, few equivalent studies have been conducted since.²

Speaker and colleagues at New York Eye and Ear Infirmary in 1991 showed that use of topical betadine during surgical preparation reduced the incidence of endophthalmitis by 75%,³ influencing the operative technique of a generation of cataract surgeons.

Recently, a study by members of the European Society of Cataract and Refractive Surgeons found that use of intracameral cefuroxime reduced the incidence of endophthalmitis by 78% compared to no intracameral cefuroxime.⁴ Despite noted flaws or shortcomings in this study, it has the potential to change the future of ophthalmology.

Many cases of endophthalmitis occur due to inoculation of organisms at the time of surgery; however, some cases may be due to introduction of pathogens through clear corneal wound leaks in the postoperative period. For this reason, endophthalmitis prophylaxis must address potential inoculations that occur both during and after surgery. Intracameral antibiotic injection may be the most appropriate route of administration to address inoculation that occurs at the time of surgery, whereas postoperative topical antibiotics are most appropriate to address inoculation that occurs postoperatively.

Intracameral antibiotic choices

Several antibiotic agents have been suggested and evaluated for intracameral prophylaxis in cataract surgery, including the aminoglycosides tobramycin and gentamicin; vancomycin; current generation fluoroquinolones; and cefuroxime.

The first antibiotics used intracamerally were the aminoglycosides, as described by Gills, Gimbel and other investigators. ^5-8 Gentamicin and tobramycin, however, can be toxic; small amounts of antibiotic can cause retinal and macular infarction with significant loss of vision.⁹ These agents also demonstrate poor efficacy against gram-positive organisms and particularly weak activity against methicillin-resistant Staphylococcus epidermidis (MRSE) and methicillin-resistant Staphylococcus aureus (MRSA), which are the first and second most common causes of endophthalmitis. Subsequently, these aminoglycosides are rarely used intracamerally for endophthalmitis prophylaxis.

Vancomycin is widely used by cataract surgeons in the United States as an intracameral antibiotic for endophthalmitis prophylaxis, often by placement in the irrigating solution.¹⁰ Although highly effective against MRSA and MRSE, intracameral use of vancomycin has been associated with an increased risk of cystoid macular edema (CME)¹¹and a slow kill curve (Figure).¹² An antibiotic that is not rapidly bactericidal and has a time-dependent rather than a dose-response kill curve is not ideal for intracameral administration, in which the drug stays in the eye for a short period.

Moreover, the Centers for Disease Control and Prevention and the American Academy of Ophthalmology have issued a joint statement recommending that vancomycin not be used for prophylaxis in ophthalmic surgery.¹³ As the mainstay of therapy for MRSA and MRSE in systemic use, vancomycin is an important antibiotic, and its routine use for intracameral prophylaxis may jeopardize the ability of infectious disease specialists to treat serious systemic disease in the future.

An antibiotic that is not rapidly bactericidal and has a time-dependent kill curve is not ideal for intracameral administration.
— Eric D. Donnenfeld, MD

Despite much interest, little evidence-based information regarding intracameral use of the current generation ophthalmic fluoroquinolones, gatifloxacin and moxifloxacin, exists, although they are the topical antibiotics of choice because of their rapid kill curves, activity against gram-positive organisms, high solubility and intraocular penetration.^14,15

In a study investigating the prophylactic use of intracameral gatifloxacin in 40 humans, 100 µg of gatifloxacin in 0.1 cc administered intracamerally in a bolus at the end of surgery was safe and well-tolerated; the authors concluded that further investigation was indicated.¹⁶ Animal studies done by the same group found that doses higher than 100 µg caused intraocular toxicity, including corneal endothelial changes and damage to the trabecular meshwork.¹⁷ Based on aqueous turnover in the anterior chamber every 90 minutes, a dilution to 100 µg would provide significant therapeutic levels for about 12 hours after administration, sufficient time for gatifloxacin to kill most organisms.

In one recently published clinical study, a preparation of 0.1 mL intracameral moxifloxacin 0.5% ophthalmic solution, containing 500 µg of moxifloxacin and administered in a bolus as the last step of phacoemulsification in 65 humans, appeared to be nontoxic in terms of visual rehabilitation, anterior chamber reaction, pachymetry and endothelial cell density.¹⁸ However, this study included no retinal evaluations, no assessment of CME and no report of contrast sensitivity results. In addition, the investigators used the ophthalmic formulation rather than the intravenous formulation of moxifloxacin, indicating two variables, the use of a new antibiotic and the use of a new delivery system.

Several clinical studies support the use of cefuroxime for intracameral endophthalmitis prophylaxis. A noncontrolled retrospective study in Sweden found a low incidence of endophthalmitis, 0.06%, after cataract surgery with use of intracameral cefuroxime.¹⁹ A subsequent noncontrolled prospective trial reported an endophthalmitis rate of 0.053% with use of intracameral cefuroxime.²⁰ Finally, the recently reported partially masked, prospective, multicenter ESCRS study reported a rate of 0.073% endophthalmitis with intracameral cefuroxime and 0.335% without.⁴

These large, well-designed clinical studies, two retrospective and one prospective, give ophthalmologists a good scientific basis for making an informed decision on the intracameral use of cefuroxime.

Figure
Vancomycin kill curve

Intracameral vancomycin has been associated with an increased risk of CME and a slow kill curve. An agent that is time-dependent is not ideal for intracameral administration, as intracamerally delivered agents stay in the eye for a short period of time. ¹²

Weighing risks and benefits

In considering the use of intracameral antibiotics, the potential benefits must be weighed against the risks. In the ESCRS study, the topical antibiotic used was levofloxacin, which is not a current generation fluoroquinolone. The relative benefit of a reduction in the risk of postoperative endophthalmitis through the administration of intracameral antibiotics may be less when compared against optimized topical antibiotics.

The potential risks of intracameral antibiotic administration include toxic anterior segment syndrome, CME, glaucoma, endothelial cell loss, dilution errors and medicolegal exposure.

Widespread interest in the use of current generation fluoroquinolones intracamerally has been demonstrated because they are so widely used for topical prophylaxis. However, there is a lack of published information from clinical trials. An unpublished study of 40 patients ¹⁶ and the published safety study by Espiritu and colleagues that includes 65 patients, ¹⁶ which combined total 105 patients with 6 months of clinical experience, do not provide the same level of evidence of efficacy and safety as the three published clinical trials of intracameral cefuroxime, with a total of 65,000 patients and 10 years of clinical experience.

Based on available evidence, cefuroxime is the best intracameral agent available. Additional safety and controlled efficacy studies are needed before another antibiotic is to be considered for intracameral use.

Topical antibiotics used in conjunction with intracameral antibiotics

Because intracameral and topical administration are necessary to treat organisms acquired at the time of surgery and through the wound postoperatively, and because no single antibiotic agent is effective against all organisms responsible for endophthalmitis, the best strategy may be to use complementary agents for intracameral and topical prophylaxis.

Based on current evidence, the best choice for topical prophylaxis is a current generation fluoroquinolone with broad-spectrum activity on the surface of the eye and rapid kill curves. The addition of the preservative benzalkonium chloride is helpful for treating organisms that are otherwise resistant.²¹ Ideally, that topical antibiotic should be matched with an intracameral agent that has good activity against the organisms that are weaknesses of the current generation fluoroquinolones, the gram-positive organisms, particularly S epidermidis and S aureus. In the ESCRS study, no cases of Streptococcus pneumoniae, one of the most virulent forms of endophthalmitis, occurred in patients who received intracameral cefuroxime, although multiple cases occurred in those who did not receive cefuroxime.

Jointly using a topical current generation fluoroquinolone with intracameral cefuroxime provides cataract surgeons with an effective means of reducing the risk of endophthalmitis.

References

Allen HF, Mangiaracine AB. Bacterial endophthalmitis after cataract extraction. II. Incidence in 36,000 consecutive operations with special reference to preoperative topical antibiotics. Arch Ophthalmol. 1974;91:3-7.

Christy NE, Sommer A. Antibiotic prophylaxis of postoperative endophthalmitis. Ann Ophthalmol. 1979;11:1261-1265.

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

Barry P, Seal DV, Gettinby G, Lees, et al; ESCRS Endophthalmitis Study Group. ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery: Preliminary report of principal results from a European multicenter study. J Cataract Refract Surg. 2006;32:407-410.

Peyman GA, Sathar ML, May DR. Intraocular gentamicin as intraoperative prophylaxis in South India eye camps. Br J Ophthalmol. 1977;61:260-262.

Gills JP. Prevention of endophthalmitis by intraocular solution filtration and antibiotics. J Am Intraocul Implant Soc. 1985;11:185-186.

Gills JP. Antibiotics in irrigating solutions. J Cataract Refract Surg. 1987;13:344.

Gimbel HV, Sun R, DeBroff BM. Prophylactic intracameral antibiotics during cataract surgery: The incidence of endophthalmitis and corneal endothelial loss. Eur J Implant Refract Surg. 1994;6:280-285.

Campochiaro PA, Conway BP. Aminoglycoside toxicity – a survey of retinal specialists. Implications for ocular use. Arch Ophthalmol. 1991;109:7:946-950.

Leaming DV. Practice styles and preferences of ASCRS members – 2003 survey. J Cataract Refract Surg. 2004;30:892-900.

Axer-Siegel R, Stiebel-Kalish H, Rosenblatt I, et al. Cystoid macular edema after cataract surgery with intraocular vancomycin. Ophthalmology. 1999;106:1660-1664.

Gritz DC, Cevallos AV, Smolin G, Whitcher JP Jr. Antibiotic supplementation of intraocular irrigating solutions. An in vitro model of antibacterial action. Ophthalmology. 1996;103:1204-1209.

A joint statement of the American Academy of Ophthalmology and the Centers for Disease Control and Prevention: The prophylactic use of vancomycin for intraocular surgery; October 1999. Available at: http://www.aao.org/education/statements/vancomycin.cfm. Accessed April 10, 2007.

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

Terai K, Joo MJ, Hyon JY, et al. Comparative efficacy of topical moxifloxacin, an expanded spectrum fluoroquinolone, versus topical ofloxacin, penicillin G and tobramycin in the treatment of experimental S. pneumoniae and P. aeruginosa keratitis in rabbits. Paper presented at: Association for Research in Vision and Ophthalmology; May 6, 2003; Fort Lauderdale, Fla.

Donnenfeld ED, Snyder RW, Kanellopoulos AJ, et al. Safety of prophylactic intracameral gatifloxacin in cataract surgery. Paper presented at: Ocular Microbiology and Immunology Group; Nov. 15, 2003; Anaheim, Calif.

Snyder RW, Chang M, Hare W, et al. Intraocular safety of gatifloxacin in a rabbit model. Paper presented at: Ocular Microbiology and Immunology Group; Nov. 15, 2003; Anaheim, Calif.

Espiritu CR, Caparas VL, Bolinao JG. Safety of prophylactic intracameral moxifloxacin 0.5% ophthalmic solution in cataract surgery patients. J Cataract Refract Surg. 2007;33:63-68.

Montan PG, Wejde G, Koranyi G, Rylander M. Prophylactic intracameral cefuroxime. Efficacy in preventing endophthalmitis after cataract surgery. J Cataract Refract Surg. 2002;28:977-981.

Wejde G, Montan P, Lundstrom M, et al. Endophthalmitis following cataract surgery in Sweden: National prospective survey 1999-2001. Acta Ophthalmol Scand. 2005;83:7-10.

Blondeau JM, Hedlin P, Borsos SD. The antimicrobial activity of gatifloxacin (GAT) with or without benzalkonium chloride (BAK) against ocular bacterial pathogens. Presented at: Association for Research in Vision and Ophthalmology; May 1-5, 2005; Fort Lauderdale, Fla.

ESCRS study and intracameral antiobiotics

As part of the Benefits and Risks of Intracameral Antibiotics expert panel review, faculty members discussed the data presented. The following features highlights of this discussion.

Effect of ESCRS study

David F. Chang, MD: The study conducted by the European Society of Cataract and Refractive Surgeons is the first prospective, randomized, controlled trial to demonstrate a benefit of antibiotic prophylaxis.¹ What impact has this study had on practice patterns in the United States?

John D. Hunkeler, MD: Ophthalmologists in the United States want to know more about the European study or conduct further study to corroborate the findings before making changes to a prophylactic regimen. The ESCRS data are preliminary. Further study should be conducted on the pockets of increased incidence of endophthalmitis; an unknown subset of information increased the risk of endophthalmitis with clear corneal surgery and with silicone lens implantation. The inconsistency of the ESCRS study may be due to its variability and lack of control.

Randall J. Olson, MD: Endophthalmitis cases may be related to factors other than the intraocular antibiotics in the ESCRS study. Good studies indicate endophthalmitis is not always an issue with sutureless clear corneal incisions. A gold standard, randomized, masked study of silicone IOLs found no increased risk of endophthalmitis associated with silicone IOLs,^2-4 which suggests the uncontrolled silicone IOL data from the ESCRS study may represent a cluster of infections.

Terrence P. O’Brien, MD: In the ESCRS study, the many varieties of surgical technique were uncontrolled, and a resistance to the agent administered has been indicated.

Chang: The rate of incidence of endophthalmitis was nearly one per 300 in the ESCRS control group. Was this the result of not using topical antibiotics preoperatively or soon enough after surgery?

John R. Wittpenn Jr., MD: In the absolute control, no preoperative antibiotics were administered, so no antibiotics were at the site of surgery upon its initiation. In addition, European surgeons use an older generation fluoroquinolone, and that fluoroquinolone was applied 18 hours after surgery. Data have shown that waiting for extended periods after surgery before applying fluoroquinolones resulted in a 13-fold increased risk of endophthalmitis. In the United States, the cost and benefit of using intracameral antibiotics to further lower endophthalmitis rates remain unknown.

Eric D. Donnenfeld, MD: It would have been optimal to use a current generation fluoroquinolone, which probably would have resulted in a lower incidence of endophthalmitis. However, a study with mild flaws is better than going forward without any useful information and using anecdotal information. Key opinion leaders will develop practice patterns based on the information and evidence reported in this study, and the comprehensive ophthalmologists will adopt them.

The future of endophthalmitis prophylaxis

Chang: The American Society of Cataract and Refractive Surgery Cataract Clinical Committee conducted an online survey of member practices earlier this year. Of the more than 1,300 members of the ASCRS who responded, 30% use intracameral antibiotics for endophthalmitis prophylaxis, with an even split between physicians adding it to the irrigation bottle and those directly injecting the antibiotic into the anterior chamber. Vancomycin was employed by 61% of those using an intracameral agent by any administration route. The majority of surgeons are administering topical antibiotics preoperatively and postoperatively, with 81% preferring a current generation fluoroquinolone. In addition, in spite of the ESCRS study results, 75% of the respondents do not plan on initiating direct intracameral antibiotic injection for routine prophylaxis. Clearly, the absence of a commercially available antibiotic solution for intracameral injection is a factor. If a commercially prepared agent were available today, would you use it?

Hunkeler: No. I am now approaching 10 years and more than 10,000 cases without a case of endophthalmitis using current generation fluoroquinolones and preservative-free epinephrine in the infusion bottle. Before I change my regimen, I would like to see evidence that the change would improve my outcomes.

O’Brien: Povidone-iodine in combination with an antibiotic is the way the standard of care has evolved. The antiseptic is still valuable together with the antibiotic; similarly, a multifaceted approach with antiseptic topically and antibiotic intracamerally to help in the immediate period of vulnerability postoperatively may be the future of endophthalmitis prophylaxis.

Wittpenn: Intracameral antibiotics may greatly benefit high-risk cases but may be unnecessary in routine cases. Using intracameral antibiotics to eliminate what appears to be approximately five cases of endophthalmitis per 10,000 patients creates costs in terms of endothelial and macular function in the other 9,995 patients. The battle is really on the ocular surface, not inside the eye. If you kill the organisms on the surface, whether before, during or after surgery, then they will not get inside the eye. The surface should be the focus. Studies on resistance, however, with the exception of Blondeau’s,⁵ indicate resistance to systemic antibiotics, not necessarily topical antibiotics. Further study on resistant organisms and topical antibiotics is necessary.

Chang: The ASCRS Cataract Clinical Committee survey shows that the majority of surgeons use topical current generation fluoroquinolones starting 1 to 3 days preoperatively and resume use immediately postoperatively, unless the eye is patched. The ESCRS study control group waited until the first postoperative day to start levofloxacin. Only one half of the control patients received a preoperative antibiotic (administered immediately before surgery). Therefore, the ESCRS study does not indicate whether intracameral cefuroxime is equal or superior to what most surgeons currently employ for endophthalmitis prophylaxis, nor does it indicate if there is further benefit to adding an intracameral injection to existing topical prophylaxis regimens.

Delivery of agents

Chang: Is there a place for antibiotics in the infusion bottle as a method of intracameral delivery?

O’Brien: That is an irrational route; the amount of fluid for every case varies significantly, and, therefore, the delivery of drug and the concentration are unknown.

Olson: Concentration can never be higher than the concentration in the IV solution. Concentrations start out lower and, with aqueous turnover as rapid as it is, intracameral antibiotics ought to be used as a bolus at the end of the case.

Donnenfeld: One advantage of using out-of-the-bottle fluoroquinolones is that dilutions are not necessary; the possibility of dilution error does not exist. Intracameral cefuroxime is barely diluted. Cefuroxime out of the IV solution is diluted 33%; a 10-fold dilution error cannot occur, unlike with vancomycin or aminoglycosides.

Which intracameral agent is best?

Olson: Cefuroxime has gone through enough study to be approved by the Food and Drug Administration, but even that could take a long time. If cefuroxime were approved and available, I would use it.

O’Brien: Based on the microbiologic evidence, if cefuroxime was available and safe, I would add it to my prophylaxis regimen because our topical agents are getting less effective. Cefuroxime has been well studied, including in vitro data, animal models and nonrandomized, then randomized human trials. I would still administer topical antibiotics, but cefuroxime would be an added agent that would augment prophylaxis in the early window of vulnerability, the first several hours after surgery. In addition, the pharmacokinetics of intraocularly administered agents is short, especially considering the 90-minute secondary aqueous formation that dilutes the agent and the enzymes and proteins in the aqueous that inactivate the agent. Intraocularly administered agents offer a very short-lived augmentation of prophylaxis.

High-risk cases

Chang: Can intracameral antibiotics be injected when there is a broken capsule, or is the risk too great?

Donnenfeld: That is one case in which the surgeon does not want to have antibiotics in the balanced salt solution because the amount of antibiotic that goes into the eye can be extraordinarily high. Because data have indicated a 10-fold increase in the incidence of endophthalmitis with a broken posterior capsule,⁶the risk-reward swings toward a benefit with intracamerally delivered agents. An antibiotic that has a tendency toward cystoid macular edema or retinal toxicity would be a bad choice, as would an aminoglycoside. Cefuroxime has demonstrated the least retinal toxicity and would be a good option, although vancomycin is a second choice.

O’Brien: I inject cefazolin in every case in which the posterior capsule is broken, based on early work for the treatment of endophthalmitis that looked carefully at the toxicity of cefazolin.^7,8

Olson: I put a suture in cases in which the posterior capsule is broken, as a means of eliminating the chance of gross contamination.

References

Barry P, Seal DV, Gettinby G, et al; ESCRS Endophthalmitis Study Group. ESCRS study of prophylaxis of postoperative endophthalmitis cafter cataract surgery: Preliminary report of principal results from a European multicenter study. J Cataract Refract Surg. 2006;32:407-410.

Fine IH, Hoffman RS, Packer M. Profile of clear corneal cataract incisions demonstrated by ocular coherence tomography. J Cataract Refract Surg. 2007;33:94-97.

Oshika T, Hatano H, Kuwayama Y, et al. Incidence of endophthalmitis after cataract surgery in Japan. Acta Ophthalmol Scand. 2007 Apr 24 [Epub ahead of print].

Nagaki Y, Hayasaka S, Kadoi C, et al. Bacterial endophthalmitis after small-incision cataract surgery. Effect of incision placement and intraocular lens type. J Cataract Refract Surg. 2003;29:20-26.

Blondeau JM, Borsos S, Hesje CK. Antimicrobial efficacy of gatifloxacin and moxifloxacin with and without benzalkonium chloride compared with ciprofloxacin and levofloxacin against methicillin-resistant Staphylococcus aureus. J Chemother. 2007;19:146-151.

Cao XR, Gong LL, Yang Y, et al. Endophthalmitis after phacoemulsification surgery. Zhonghua Yan Ke Za Zhi. 2005;41:519-522. [Article in Chinese.]

Ficker L, Meredith TA, Gardner S, bWilson LA. Cefazolin levels after intravitreal injection. Effects of inflammation and surgery. Invest Ophthalmol Vis Sci. 1990;31:502-505.

Martin DF, Ficker LA, Aguilar HA, et al. Vitreous cefazolin levels after intravenous injection. Effects of inflammation, repeated antibiotic doses, and surgery. Arch Ophthalmol. 1990;108:411-414.