The ESCRS study of the prophylaxis of postoperative endophthalmitis after cataract surgery¹ created quite a stir among ophthalmologists. Finally, there was a prospective, randomized, placebo-controlled study demonstrating a benefit of intracameral antibiotics in preventing endophthalmitis. Specifically, the report showed that an intracameral injection of cefuroxime at the end of cataract surgery lowered the risk of endophthalmitis by a factor of five. This landmark study evaluated nearly 14,000 patients from 24 centers in nine European countries. Additional risk factors for endophthalmitis gleaned from the study included clear corneal wounds and silicone IOLs.²

Before we surgeons all instruct our surgical nurses to take 750 mg of cefuroxime powder and dilute it to a concentration of 1 mg/0.1 mL of balanced salt solution for our next cataract cases, we need to examine the study closely and understand its implications.

TOPICAL ANTIBIOTICS
Fourth-Generation Fluoroquinolones
The subjects of the ESCRS study were not treated with what we consider the standard of care in the US for surgical prophylaxis, fourth-generation fluoroquinolones, both pre- and postoperatively. Although all patients received preoperative povidone-iodine and postoperative levofloxacin (a third-generation fluoroquinolone), only two of the four groups received preoperative levofloxacin. It has been demonstrated in several studies that the fourth-generation fluoroquinolones, moxifloxacin and gatifloxacin, have an improved spectrum of coverage, higher potency, delayed antibiotic resistance, and better tissue penetration (especially moxifloxacin) when compared with second- and third-generation fluoroquinolones.³

An animal study conducted at the University of Pittsburgh⁴ showed that topical moxifloxacin could prevent postoperative endophthalmitis in eyes that had been inoculated with Staphylococcus aureus. The eyes that did not receive topical moxifloxacin all developed endophthalmitis due to the number of organisms inoculated in the eye. None of the eyes that received topical moxifloxacin before and after inoculation developed endophthalmitis. This striking study illustrated just how powerful topical antibiotics can be in the prevention of endophthalmitis. It showed that a topical agent can penetrate the eye at a high enough concentration to reach therapeutic, bacteriocidal levels. It is unknown what the ESCRS study's results would have been had all patients received pre- and postoperative moxifloxacin or gatifloxacin.

Safety
The greatest advantage of topical antibiotic prophylaxis over intracameral antibiotics is safety. There is no concern of dilutional error, toxic anterior segment syndrome, endothelial toxicity, or the introduction of potentially contaminated substances into the anterior chamber. Antibiotics for intracameral use must be mixed correctly 2,700 times to reduce severe visual loss from endophthalmitis in one patient while avoiding toxic ocular effects in noninfected patients.⁵ When mixed in the appropriate concentration, cefuroxime has not demonstrated any toxicity to the corneal endothelium or retina.⁶ The pH of the solution is 7.42, and the osmolality is 311 mOsm/kg, well within the suitable range for humans.5 Also, another study has shown no increased incidence of cystoid macular edema in patients who received intracameral cefuroxime.⁷

An additional issue in regard to an antibiotic's safety is a patient's potential hypersensitivity to the drug. Someone who is allergic to a topical agent will typically have contact dermatitis or conjunctivitis but will not develop an anaphylactic reaction. Patients with hypersensitivity to an intracameral agent, such as cefuroxime, can actually develop systemic anaphylaxis with associated morbidity and possible mortality, as reported by Villada et al.⁸ They described a patient with a history of allergy to oral ampicillin who received 1 mg of cefuroxime intracamerally (the same concentration as used in the ESCRS study) at the conclusion of an uncomplicated phaco case. Five minutes later, the patient developed problems breathing and went into hypovolemic shock due to the anaphylactic reaction. Fortunately, the anesthesiologist was present in the recovery room and quickly administered intravenous methylprednisolone, ephedrine, 3 L of Ringer's lactate solution, and antihistamines. The patient recovered from this life-threatening allergic reaction in half an hour but was admitted to the hospital for observation. Referring to this case, Liu et al⁹ stated, "conceptually speaking, intracameral antibiotic administration in a patient with a history of antibiotic allergy is highly akin to the direct intravenous route of administration in terms of bioavailability, particularly in the face of a disrupted blood-aqueous barrier during phacoemulsification."

The rate of any hypersensitivity to a cephalosporin such as cefuroxime is reported to be 1 to 3.¹⁰ The rate of anaphylaxis with cephalosporins is reported to be 0.1 to 0.0001.¹¹ With approximately 2.5 million cataract surgeries performed each year in the US, as many as 2,500 patients per year could potentially develop anaphylaxis if every case were performed according to the ESCRS study guidelines and each patient received intracameral cefuroxime. Montan and colleagues⁶ continue to use cefuroxime on a wide-scale basis in Sweden by pretreating patients with a history of anaphylaxis to this antibiotic with oral antihistamines. In the ESCRS study, patients were excluded if they were allergic to penicillins and cephalosporins. What if the patient has not been exposed to enough antibiotics, however, to realize a hypersensitivity exists?

Compliance
Topical antibiotic prophylaxis depends on patients' compliance in order to be effective. Intracameral antibiotics have the advantage of being placed into the anterior segment at the conclusion of surgery. Moreover, these agents are effective if they have a sufficiently high concentration for an adequate length of time with a spectrum of activity that encompasses the organisms that enter the anterior chamber during or soon after cataract surgery.

SPECTRUM OF ACTIVITY
The decision to use cefuroxime in the ESCRS study was based on work by Montan et al,¹² who showed a statistically significant reduction in postoperative endophthalmitis in patients who had received intracameral cefuroxime in a prospective, uncontrolled, 3-year survey. Cefuroxime is a second-generation cephalosporin with fair antibiotic coverage against gram-positive organisms and some gram-negative organisms. It has a time-dependent killing action, and its bacteriocidal effect is due to interference with cell wall synthesis. In terms of bacterial susceptibility, cefuroxime has good activity against most Staphylococcus and Streptococcus species, Escherichia coli, Proteus species, Propionibacterium species, Klebsiella, and Haemophilus influenzae. There are significant gaps in coverage, however. Cefuroxime does not cover methicillin-resistant S. aureus (MRSA), some Enterococcus strains, and Pseudomonas. It is important to note that patients from long-term nursing homes were not eligible to participate in the ESCRS study, because this patient population is known to have a greater risk of colonization with resistant strains of bacteria such as MRSA.

A study performed at the University of Pittsburgh showed that moxifloxacin and gatifloxacin provided higher susceptibility to Bacillus, Enterococcus, and gram-negative bacteria than cefuroxime using actual endophthalmitis isolates and equal susceptibility for Staphylococcus and Streptococcus strains. The researchers concluded that, in regard to the choice of an intracameral agent, fourth-generation fluoroquinolones might provide more broad-spectrum coverage of endophthalmitis-causing bacteria than cefuroxime.¹³

EFFICACY OF CEFUROXIME
Due to the constant turnover of aqueous, the concentration of a drug in the anterior chamber would decrease by one half in 70 minutes, although it might decrease even more rapidly due to quicker aqueous dynamics in the postoperative inflamed eye.¹⁴ A study evaluating the pharmacokinetics of intracameral cefuroxime determined that the concentration declined by a factor of four in 1 hour.⁵ Cefuroxime has a slower, time-dependent bacteriocidal action, and, therefore, a certain amount of time must pass before bacteria are killed, even if the concentration of antibiotic is very high. In contrast, agents such as the fluoroquinolones are concentration dependent.

A kinetics of kill study was performed with cefuroxime against staphylococcal ocular isolates.¹⁵ It showed that less than one log kill was achieved in 3 hours. The researchers contrasted this result to the kinetics of kill of moxifloxacin, which showed a greater than three log kill (> 99.9) after less than 2 hours. This difference may explain the development of endophthalmitis secondary to a cefuroxime-susceptible strain of S. aureus in a patient who received intracameral cefuroxime at the end of surgery.¹¹

CONCLUSION
The authors of the ESCRS study on the prophylaxis of postoperative endophthalmitis after cataract surgery should be congratulated for undertaking this important task. They designed a partially masked, randomized, placebo-controlled, multinational clinical study to prospectively evaluate the effect of intracameral cefuroxime and/or perioperative topical levofloxacin on postoperative endophthalmitis. Although the total study size goal was 35,000 patients, the study was halted at the end of 2005 after the recruitment of only 13,698 patients, because a clearly beneficial effect from the use of intracameral cefuroxime had been observed.

There are several factors we need to keep in mind before we change our practice patterns in 2007. First, certain groups of patients were ineligible to participate in the ESCRS study, including nursing home patients. In addition, cefuroxime is a slow, time-dependent killer that is ineffective against MRSA, Pseudomonas, and some Enterococcus species. There are several issues of safety with this agent, including reports of severe anaphylaxis. Finally, ESCRS study patients did not receive adjunctive topical fourth-generation fluoroquinolones, which have an improved spectrum of coverage, higher potency, delayed antibiotic resistance, and better tissue penetration compared with the third-generation fluoroquinolone used in the ESCRS study.

Deepinder K. Dhaliwal, MD, is Associate Professor, University of Pittsburgh School of Medicine; Director, Cornea & External Disease Service, UPMC Eye Center; Director, Refractive Surgery Service, UPMC Eye Center; and Medical Director, UPMC Laser/Aesthetic Center, all in Pittsburgh. Dr. Dhaliwal may be reached at (412) 647-2214; dhaliwaldk@upmc.edu.

1. Barry P, Seal D, Gettinby G, et al. ESCRS study of prophylaxis of post-operative endophthalmitis after cataract surgery: preliminary report of principal results from a European multicentre study. J Cataract Refract Surg. 2006;32:407-410.
2. Barry PJ. ESCRS: study design and results. Paper presented at: The AAO Annual Meeting; November 12, 2007; Las Vegas, NV.
3. Kim DH, Stark WJ, O' Brien TP, et al. Aqueous penetration and activity of moxifloxacin 0.5 ophthalmic solution and gatifloxacin 0.3 ophthalmic solution in cataract surgery patients. Ophthalmology. 2005;112:1992-1996.
4. Kowalski R, Romanowski E, Mah F, et al. Topical prophylaxis with moxifloxacin prevents endophthalmitis in a rabbit model. Am J Ophthalmol. 2004;138:33-37.
5. Alfonso EC, Flynn HW Jr. Controversies in endophthalmitis prevention. The risk for emerging resistance to vancomycin. Arch Ophthalmol. 1995;113:1369-1370.
6. Montan PJ, Wejde G, Setterquist H, et al. Prophylactic intracameral cefuroxime. Evaluation of safety and kinetics in cataract surgery. J Cataract Refract Surg. 2002;28:982-987.
7. Gupta MS, McKee HD, Saldana M, Stewart OG. Macular thickness after cataract surgery with intracameral cefuroxime. J Cataract Refract Surg. 2005;31:1163-1166.
8. Villada JR, Vicente U, Javaloy J, Alio JL. Severe anaphylactic reaction after intracameral antibiotic administration during cataract surgery. J Cataract Refract Surg. 2005;31:620-621.
9. Liu DT, Lee VY, Chan VC, Lam DS. Severe anaphylactic reaction after intracameral antibiotic administration during cataract surgery. J Cataract Refract Surg. 2006;32:188.
10. Anne S, Reisman RE. Risk of administering cephalosporin antibiotics to patients with histories of penicillin allergy. Ann Allergy Asthma Immunol. 1995;74:167-170.
11. Kelkar PS, Li JT-C. Cephalosporin allergy. N Engl J Med. 2001;345:804-809.
12. Montan PJ, Wejde G, Koranyi G, Rylander M. Prophylactic intracameral cefuroxime: efficacy in preventing endophthalmitis after cataract surgery. J Cataract Refract Surg. 2002;28:977-981.
13. Contreras JE, Kowalski RP, Mah FS, Thompson P. Does cefuroxime provide better in vitro susceptibility that the 4th generation fluoroquinolones and cefazolin? Paper presented at: The OMIG Meeting; November 10, 2006; Las Vegas, NV.
14. Gritz DC, Cevallos AV, Smolin G, Whitcher JP Jr. Antibiotic supplementation of intraocular irrigating solutions. An in vitro model of antibacterial action. Ophthalmology. 1996;103:1204-1208.
15. O'Brien TP, Arshinoff SA, Mah FS. Perspective on cefuroxime and the recent ESCRS postoperative endophthalmitis (POE) study. Paper presented at: The OMIG Meeting; November 10, 2006; Las Vegas, NV.