Recommendations for topical antibiotic prophylaxis

Unlike internal medicine infectious disease specialists, ophthalmologists have the advantage of being able to place an antibiotic agent directly on the target tissue (topically) without excessive direct concern for issues such as volume of distribution or the metabolism of the drug. Whether the prophylactic effect of topical administration of antibiotics in cataract surgery can be augmented by the addition of intracameral administration remains a topic of discussion.

West and coworkers, through retrospective examination of Medicare claims data for 500,000 surgeries over 8 years, concluded that the incidence of endophthalmitis after cataract surgery increased between 1994 and 2001.¹ However, surgical techniques and the arsenal for antibiotic prophylaxis have changed since the beginning of that study. In more recent data from the Bascom Palmer Eye Institute between 2000 and 2005, the rate of endophthalmitis after cataract surgery did not increase significantly (Table).²

Risk factors for endophthalmitis between 2000 and 2005 included systemic immunosuppression, the method of operative preparation, intraoperative complications such as vitreous loss, perioperative factors such as the presence of surface bacteria, wound construction factors such as wound leak and inferior incision placement, and the presence of chronic blepharitis.

The role of topical antibiotic prophylaxis is to reduce the colonization with the organisms of the periocular flora on the ocular surface, as the patient’s own flora are often the cause of endophthalmitis.³ Other studies support that gram-positive, coagulase-negative organisms, notably Staphylococcus epidermidis, are the predominant causative agents in cases of endophthalmitis.^4,5

Goals of prophylaxis

The goals of prophylaxis must be taken into account when considering a regimen to reduce the risk for infection.

One goal is to limit the number of organisms entering the eye, which can be accomplished by reducing the number of organisms on the ocular surface, by preventing intraoperative intraocular bacterial contamination and by preventing postoperative bacterial contamination through the wound.

One widely accepted way to reduce organisms on the ocular surface is to apply a 10% povidone-iodine solution on the periocular skin and 5% povidone-iodine solution directly on the conjunctiva. Data show that 5% povidone-iodine has a broad spectrum of action and requires short contact time with microorganisms to be effective; use of 5% povidone-iodine alone was shown to reduce the incidence of culture-positive endophthalmitis threefold, from 0.18% to 0.06% (P <>⁵ Apt and colleagues found that 5% povidone-iodine reduced the number of bacterial colonies by 91% (P < .05)="" and="" the="" number="" of="" species="" by="" 50%="">P <>⁶ In another study, the addition of a preoperative topical antibiotic was shown to further enhance the efficacy of povidone-iodine.⁷

A recent review of published studies on endophthalmitis found that use of topical povidone-iodine preoperatively is the most strongly supported of prophylactic techniques.⁸

Administration of a topical antiseptic, with its direct contact mechanism of action and immediate effect, is a good complement to the use of a topical antibiotic, which has an effect on organism replication that is more dependent on time and kill-curve kinetics.

The goals of prophylaxis must be taken into account when considering a regimen to reduce the risk for infection. — Terrence P. O’Brien, MD

A second goal of antibiotic prophylaxis is to eradicate the organisms that may enter the eye. Natural host defense mechanisms in the eye are efficient at removing inoculations to a degree, but a therapeutic concentration of antibiotic is needed when the contamination exceeds the capacity of the aqueous humor to adequately clear an organism. Possible modes of administration include subconjunctival injections, placement of antibiotics in the infusion fluid, oral systemic administration and topical administration.

Although a recent study by members of the European Society of Cataract and Refractive Surgeons concluded that intracameral administration of cefuroxime reduced the incidence of postoperative endophthalmitis, the preparation used for intracameral administration in the study is neither commercially available in the United States nor approved for ophthalmic use.⁹ Because of the need for compounding antibiotics, errors in dilution or loss of sterility may occur. Rarely, patients exhibit hypersensitivity to beta lactam antibiotics. In addition, this cephalosporin is not effective against methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE), Enterococcus faecalis or Pseudomonas aeruginosa. With multiple doses prepared in a single container, contamination with P aeruginosa may occur.

With a compounded antibiotic preparation administered intraocularly, the possibility of toxic anterior segment syndrome (TASS) exists. TASS is an acute, noninfectious sterile inflammatory condition of the anterior segment that results from a number of causes, including irrigating solutions or medications outside a tolerable range of pH, medications in toxic concentrations, cleaning agents, organic material biofilms or toxic residues.¹⁰ An increased incidence of cystoid macular edema has also been reported in relation with use of intracameral antibiotics in the infusion fluid.¹¹

Role of fluoroquinolones

The ideal antibiotic agent, which could be used in conjunction with povidone-iodine, would have the four “killer Bs”: a broad spectrum of activity, a bactericidal mechanism of action, biocompatibility and bioavailability. Bioavailability is especially important for antibiotic prophylaxis with cataract surgery; to be effective, an agent must penetrate the aqueous and, preferably, the vitreous humor.

For this reason, fluoroquinolones have emerged in Europe and the United States as the mainstay of topical cantibiotic prophylaxis. The two current generation ophthalmic 8-methoxy fluoroquinolones available in the United States, moxifloxacin and gatifloxacin, are particularly active against gram-positive species while also maintaining an excellent gram-negative effect. These agents are effective against endophthalmitis isolates that were resistant to the earlier generation fluoroquinolones ciprofloxacin, ofloxacin and levofloxacin.¹² The current generation fluoroquinolones are more efficacious against organisms that cause endophthalmitis in humans, notably S epidermidis, S aureus and S pneumoniae, than previous generations.

Increased resistance to fluoroquinolones has been reported in keratitis, conjunctivitis and endophthalmitis isolates (Figure).^13-15 Increasing antimicrobial resistance has been reported worldwide.¹⁶

A study of 111 coagulase-negative staphylococcal isolates recovered from patients with endophthalmitis from 1990 to 2004 found the agent with the best activity against the organisms that were recovered was vancomycin, and increased resistance to fluoroquinolones was observed.²

Studies of ocular pathogens indicate many bacteria now have resistance to multiple types of drugs, including fluoroquinolones, cephalosporins and methicillin. In a 2001 study, none of the endophthalmitis isolates were susceptible to the older fluoroquinolones.¹⁷

A study by Blondeau and colleagues showed that the current generation fluoroquinolone gatifloxacin with benzalkonium chloride (BAK) has lower minimum inhibitory concentrations against a number of organisms than gatifloxacin without BAK.¹⁸ The combination of agent plus BAK was more effective than the agent alone; all clinical specimens of S pneumoniae tested, as well as a number of other strains, had lower MICs for the gatifloxacin solution with BAK than the drug without BAK.

A similar study showed that the topicala agent gatifloxacin 0.3% with BAK had a faster kill curve than the fluoroquinolone agent moxifloxacin 0.5% alone against several strains of Staphylococcus. The strains were inoculated to the two antibiotics, and serially diluted samples were incubated for 72 hours at 35° C. Test samples were assayed at 15, 30 and 60 minutes.¹⁹

Gatifloxacin 0.3% killed the bacterial inoculum completely at 30 minutes in 16 of 17 test strains. At 60 minutes, no bacterial colony was recovered from topical gatifloxacin 0.3% in all strains. Moxifloxacin 0.5% reduced the bacterial inoculum by 60 minutes in all strains, but complete killing within 60 minutes was observed in only one strain.¹⁹

Figure Emerging resistance to fluoroquinolones Bacterial isolates from ocular infections have been showing increasing resistance to fluoroquinolones.13-15

Bioavailability

The bioavailability of an antibiotic can be assessed on the basis of how high a concentration it reaches in the tears, the cornea or other ocular tissues. Topical administration results in significant concentrations achieved in the tear film and on the cilia and meibomian glands. Penetration into the cornea can also be achieved, with subsequent distribution providing potentially therapeutic levels in the aqueous humor.

Solomon and colleagues compared aqueous humor concbentrations of two topically administered current generation fluoroquinolones and found that moxifloxacin achieved roughly twice the concentration of gatifloxacin in the aqueous humor in one study.²⁰ Additionally, moxifloxacin achieved a maximum concentration (Cmax) of 10 times more than the MICs of most endophthalmitis-causing organisms. ²⁰

A potentially protective concentration of moxifloxacin can be obtained in the aqueous humor of human patients with topical dosing prior to cataract surgery.²¹ Aqueous humor concentrations of 1.8 µg/mL for moxifloxacin and 0.48 µg/mL for gatifloxacin were achieved. The Cmax of moxifloxacin exceeded the known MICs of the organisms that most frequently caused endophthalmitis.¹³

Topical administration of a current generation fluoroquinolone may prevent endophthalmitis even with a huge inoculum. In one animal study, one drop of moxifloxacin or saline solution was administered at 60, 45, 30 and 15 minutes before injection of a broth containing 0.025 mL (5 × 104 colony-forming units) of S aureus into the anterior chamber of rabbits. After injection, four drops of moxifloxacin or saline solution were administered over 24 hours. At an examination at 24 hours, the moxifloxacin-treated rabbits did not develop clinical signs of endophthalmitis, while a large proportion of animals in the saline-treated group had signs of endophthalmitis.²²

Once an organism reaches the vitreous, topical application of antibiotics is probably not efficacious to prevent infection. Costello and colleagues concluded that penetration of topically applied moxifloxacin and gatifloxacin into the vitreous in the uninflamed eye was not at significant levels to be protective against endophthalmitis.²³

Conclusion

Endophthalmitis prophylaxis is a challenging subject; prophylaxis does not equal treatment, and effective prophylaxis requires continual evolution of maneuvers in a multisystem approach.

A single intracameral dose alone will never replace frequent application of perioperative antibiotics. Topical administration of antibiotics preoperatively in combination with antiseptic has evolved as a standard of practice to reduce surface colonization and the likelihood of intraocular contamination. Topical administration in the early postoperative period is necessary to sustain delivery of the agent during the period of vulnerability and opportunity for infection. Intracameral delivery in select cases may be beneficial and perhaps may evolve as a routine standard with the appropriate demonstration of safety and efficacy. Finding the optimal agent will require further study and more comprehensive assessment of potential toxicity.

References

1. West ES, Behrens A, McDonnell PJ, et al. The incidence of endophthalmitis after cataract surgery among the US Medicare population increased between 1994 and 2001. Ophthalmology. 2005;112:1388-1394.
2. Miller D, Flynn PM, Scott IU, et al. In vitro fluoroquinolone resistance in staphylococcal endophthalmitis isolates. Arch Ophthalmol. 2006;124:479-483.
3. Speaker MG, Milch FA, Shah MK, et al. Role of external bacterial flora in the pathogenesis of acute postoperative endophthalmitis. Ophthalmology. 1991;98:639-649.
4. Han DP, Wisniewski SR, Wilson LA, et al. Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol. 1996;122:1-17.
5. Speaker MG, Menikoff JA. Prophylaxis of endophthalmitis with topical povidone-iodine. Ophthalmology. 1991;98:1769-1775.
6. Apt L, Isenberg S, Yoshimori R, et al. Chemical preparation of the eye in ophthalmic surgery. III. Effect of povidone-iodine on the conjunctiva. Arch Ophthalmol. 1984;102:728-729.
7. Apt L, Isenberg SJ, Yoshimori R, et al. Outpatient topical use of povidone-iodine in preparing the eye for surgery. Ophthalmology. 1989;96:289-292.
8. Ciulla TA, Starr MB, Masket S. Bacterial endophthalmitis prophylaxis for cataract surgery: An evidence-based update. Ophthalmology. 2002;109:13-24.
9. Barry P, Seal DV, Gettinby G, 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.
10. Mamalis N, Edelhauser H, Hellinger W, et al. Toxic anterior segment syndrome (TASS) outbreak final report – September 22, 2006. Available at http://www.ascrs.org/press_releases/Final-TASS-Report.cfm. Accessed April 10, 2007.
11. Axer-Siegel R, Stiebel-Kalish H, Rosenblatt I, et al. Cystoid macular edema after cataract surgery with intraocular vancomycin. Ophthalmology. 1999;106:1660-1664.
12. Mather R, Karenchak LM, Romanowski EG, et al. Fourth generation fluoroquinolones: New weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133:463-466.
13. Mah F. New antibiotics for bacterial infections. Ophthalmol Clin North Am. 2003;16:11-27.
14. Marangon FB, Miller D, Romano A, et al. Emergence of quinolone resistance among methicillin sensitive Staphylococcus aureus keratitis and conjunctivitis isolates. Presented at: Association for Research in Vision and Ophthalmology; May 5, 2002; Fort Lauderdale, Fla.
15. Ritterband DC, Farquhar A, Shah M, et al. Are second generation fluoroquinolone antibiotics losing their competitive edge in precataract surgery prophylaxis? Presented at: Association for Research in Vision and Ophthalmology; May 6, 2002; Fort Lauderdale, Fla.
16. Smith RD, Coast J. Antimicrobial resistance: A global response. Bull World Health Organ. 2002;80:126-133.
17. Kowalski RP, Karenchak LM, Romanowski EG. Infectious disease: Changing antibiotic susceptibility. Ophthalmol Clin North Am. 2003;16:1-9.
18. 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.
19. Eser I, Hyon J, Hose S, O’Brien TP. Comparative antimibcrobial efficacy of preserved and preservative-free topical fourth-generation fluoroquinolones against various strains of Staphylococcus. Presented at: Association for Research in Vision and Ophthalmology; April 25-29, 2004; Fort Lauderdale, Fla.
20. Solomon R, Donnenfeld ED, Perry H, et al. Aqueous humor concentrations from topically applied ocular fluoroquinolones. Poster presented at: Association for Research in Vision and Ophthalmology; April 25-29, 2004.
21. Kim DH, Stark WJ, O’Brien TP, Dick JD. Aqueous penetration and biological activity of moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% solution in cataract surgery patients. Ophthalmology. 2005;112:1992-1996.
22. Kowalski RP, Romanowski EG, Mah FS, et al. Intracameral Vigamox (moxifloxacin 0.5%) is non-toxic and effective in preventing endophthalmitis in a rabbit model. Am J Ophthalmol. 2005;140:497-504.
23. Costello P, Bakri SJ, Beer PM, et al. Vitreous penetration of topical moxifloxacin and gatifloxacin in humans. Retina. 2006;26:191-195.

Topical antiobiotics and endophthalmitis prophylaxis Prophylaxis with topical antibiotics Chang: Regardless of whether intracameral antibiotics are used as an adjunct measure, when should topical antibiotics be started? Wittpenn: The assumption that endophthalmitis occurs primarily at the time of surgery may not be correct. Data from Speaker’s study show that bacteria were identical to the flora,1 but studies have yet to indicate when in the surgical process organisms are most often introduced. With short surgical times, high volumes and decreasing reimbursement, some of the fundamental goals of sterilizing the ocular surface at the time of surgery and maintaining that sterility until healing may be overlooked. Bucci’s studies show that preoperative ofloxacin in combination with lid scrubs had a higher percentage of sterile ocular surfaces prior to the initiation of povidone-iodine than lids that received lid scrub alone and than those that received antibiotic alone.2 O’Brien: Because of the current generation fluoroquinolones’ speed of kill, many surgeons have begun dosing on the day of surgery. Based on the levels achieved and the kill curve kinetics, day-of-surgery dosing appears to be reasonably efficacious, although some suggest that dosing 1 or 2 days before surgery is more protective. Wittpenn: When dosing the day of or the time of surgery, the ability to concentrate an appreciable amount of drug in the corneal stroma is lessened. Both moxifloxacin and gatifloxacin accumulate in the cornea at high levels if given sufficient time. Studies have looked at this accumulation after 2 to 3 days, or 1 to 2 days, but no study has evaluated this after 1 hour. Most data indicate administration 1 to 3 days preoperatively is the most efficacious.3-5 Olson: Dosing 1 day prior to surgery should be efficient, as most surgical schedules cannot accommodate 2 to 3 days preoperatively. Chang: To improve postsurgical sterilization of the surface of the eye, I administer povidone-iodine at the end of the case as well as prior to surgery. What is your postoperative regimen? Olson: In the past, I have continued postoperative antibiotics for 1 week, but based on emerging data in which a majority of endophthalmitis cases present in the second week postoperatively, I continue antibiotics for 2 weeks.6 Wittpenn: I continue postoperative antibiotics until the conjunctiva has sealed over the external entrance to the wound, which can occur within 4 to 5 days. When I perform clear corneal surgery, I continue postoperative antibiotics for approximately 2 weeks. J.E. “Jay” McDonald, MD: We indicate that patients should continue antibiotics for at least 1 week. O’Brien: I advocate an early pulse dosing schedule. For the first 24 to 48 hours postoperatively, I dose antibiotics every 2 hours to protect against one mode of spike that occurs then. After that initial 48 hours, I dose antibiotics four times daily for 1 week, although the rationale exists to continue dosing for 10 to 14 days. McDonald: At many 3-hour postoperative examinations, we found that a significant number of incisions that were sealed immediately following clear corneal surgery had developed leaks; subsequently, at my practice, we also dose every hour for that first day. Hunkeler: Has there been scientific evidence indicating that waiting 5 minutes between drop application is optimal for the patient? Olson: Pharmacologic literature indicates no direct linear relationship, but little dilution of one drop over the other after 5 minutes occurs. Three minutes is probably acceptable, but significant dilution issues occur when one drop is administered immediately after the other.7 O’Brien: Three minutes is fairly good in terms of dilution and more realistic in terms of compliance. Wittpenn: Patients are often concerned about the amount of medication making it into the eye and waste drops by administering multiple drops to ensure enough made it into the eye. We educate patients that the tear film holds 10 mcL and the drop is 50 mcL, so if any part of the drop makes it into the eye, it is sufficient. Resistance to agents Donnenfeld: The ESCRS study is a good model indicating where current generation fluoroquinolones will be in 3 or 4 years. The topical antibiotics available now are going to be the only agents available until after 2010, and the resistance profile seen with the third-generation fluoroquinolones will be exactly the same resistance patterns that will be seen with the current generation fluoroquinolones several years from now. Unless antibiotic prophylaxis strategies are developed that augment topical therapy, rates of endophthalmitis will continue to increase as resistance to the current generation fluoroquinolones invariably will occur. Ophthalmologists will be forced to use intracameral antibiotics. McDonald: In my experience, no Staphylococcus organism can survive topically applied bacitracin. Ointment in the eye can result in toxic anterior segment syndrome (TASS), but a well-constructed wound and continued nighttime bacitracin 3 days before surgery and 1 week after stops infection. Olson: Ointment is a problem in patients who undergo clear corneal surgery without a suture; many cases of TASS have occurred in the research being conducted at the Moran Eye Center. Once ointment is in the eye, it becomes a little spherule that is chronically inflammagenic. Ointment should not be used after surgery if the wound was not sutured. Wittpenn: Blondeau’s work with topical agents and BAK combinations is encouraging in the fight against methicillin-resistant Staphylococcus aureus (MRSA) organisms.8 However, this is not a solution, it only buys time before organisms become resistant to the BAK and topical agent combinations. Compliance Hunkeler: I have instructed patients to start an antibiotic and a nonsteroidal 3 days preoperatively, but I cannot ensure compliance. Patients who are not compliant preoperatively are likely to be noncompliant postoperatively as well. Patients without prior experience of self-administration should be shown the correct way to administer drops. Chang: If ophthalmologists are relying on a topically applied antibiotic to provide perioperative prophylactic coverage, then compliance is a potential issue. That is one advantage of an intracamerally administered agent. Hunkeler: Training the patient preoperatively on how to administer drops without touching the backside of the incision might provide better outcomes as well. How do you educate patients and caregivers in the use of medication? Olson: A breakdown in communication often occurs between doctor and patient. At the Moran Eye Center, a complete set of instructions is written up based on the surgeon’s orders given to the nursing staff, who discuss this with the patient and other caregivers, and can give instruction on how best to administer drops. We also have the pharmacist reiterate this information, and the pharmacist calls the next day to follow up, letting us know of any issues or concerns. O’Brien: At Bascom Palmer, patients watch an instruction video in the preoperative period and the instructions are re-emphasized in the postoperative area. The video goes over drop application in detail, and we provide written documentation of the frequency with which the drops should be administered. Chang: It is a challenge to come up with a topical-medication regimen for the patient that is clinically rational, but also patient friendly in terms of compliance. With multiple eye drop medications, including antibiotics, steroids and NSAIDs, many patients get confused. Written dosing schedules and information are important, and it also helps to include pictures of the bottles on these written instructions. Wittpenn: Approximately 1 week prior to surgery, the patient comes in and receives instruction on application and dosing from a nurse, as well as written instructions. With this instruction 1 week preoperatively, proper procedure is fresh in the minds of patients. It also allows me to get better IOL measurements through a pupil that has not been dilated. I have also found pulse dosing confuses many patients, particularly when a patient is on an NSAID that should not be dosed every 2 hours, while the antibiotic should. References Speaker MG, Milch FA, Shah MK, et al. Role of external bacterial flora in the pathogenesis of acute postoperative endophthalmitis. Ophthalmology. 1991;98:639-650. Bucci FA Jr. Presented at the annual meeting of the Association for Research in Vision and Ophthalmology. 2000; Fort Lauderdale, Fla. Wittpenn JR, et al. Presented at the annual meeting of the American Academy of Ophthalmology. 2004; New Orleans, La. McCulley JP, Caudle D, Aronowicz JD, Shine WE. Fourth-generation fluoroquinolone penetration into the aqueous humor in humans. Ophthalmology. 2006;113:955-959. [Epub 2006 Apr 17.] Aronowicz JD, et al. Presented at the annual meeting of the Association for Research in Vision and Ophthalmology. 2005; Fort Lauderdale, Fla. Moshirfar M. Feiz V, Vitale AT, et al. Endophthalmitis after uncomplicated cataract surgery with the use of fourth-generation fluoroquinolones: A retrospective observational case series. Ophthalmology. 2007;114:686-691 [Epub ahead of print Dec. 20, 2006]. Sultana Y, Jain R, Aqil M, Ali A. Review of ocular drug delivery. Curr Drug Deliv. 2006;3:207-217. 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.