Intracameral Cefuroxime at an Impasse?

ESCRS's landmark study clarifies cefuroxime's potential in the battle against endophthalmitis. But why are the findings still largely unheeded?

By Francis S. Mah, MD

For all the advances that have transformed cataract surgery into an extremely efficient, safe, reproducible, reliable and precise means of resolving a condition that can reduce quality of life and even lead to blindness, there still remains one scourge: endophthalmitis. Despite continual improvements in the prevention of postoperative infections, revolutionary innovations such as wound architecture, povidone-iodine use and postoperative use of ever-improving anti-infectives, endophthalmitis does still occur, albeit rarely.

Because of its relative rarity and the many variables in surgical styles, the condition's prophylaxis has been difficult to investigate. The bold study initiated by the European Society of Cataract and Refractive Surgeons (ESCRS) and published in 2007 sought to create another revolution in the prevention of postoperative infections through the use of intracameral prophylactic antibiotics and by comparing this technique to conventional topical application. Although many pockets of adoption of the ESCRS's findings have occurred, especially in Europe, the findings have been met with a surprising amount of criticism. Why is intracameral cefuroxime still controversial?

The cataract surgeon's nemesis: endophthalmitis. ALL IMAGES COURTESY OF THE AUTHOR

Antimicrobials Evolution

Infection origin is almost always exogenous, as shown by Speaker et al., which means the infecting organism gains access to the inner eye during surgery or early in the postoperative period prior to complete re-epithelialization of the incision. Aseptic technique and antisepsis with povidone-iodine are the keys to reducing the operative risk, in addition to others; ocular hygiene and topical antibiotic agents have been shown to significantly reduce the postoperative risk.

Despite attempts to sterilize the ocular surface prior to surgical intervention, several studies have confirmed that bacteria almost always contaminate the intracameral space during the procedure.^1,2 Further, and probably more importantly, wound security or lack of it may allow ingress of bacteria in the early postop period, regardless of suture presence or removal in the early postoperative period.^3,4 Although antimicrobial agents have dramatically improved over time, many questions remain regarding timing of initiation, method of application, formulations and concentrations of drug, and length of optimal use.

Topical antibiotic therapy following the conclusion of cataract surgery has been the mainstay for decades due to ease of use, commercial availability and the theory of eliminating the pathogen at its source — the periocular area. Retrospective analysis has shown topical agents to be of benefit; however, a prospective, randomized, statistically rigorous study has never been reported in the literature to prove this practice. Possible limitations of topical applications may include limited ocular penetration and limited duration of effect.

An example of P. acnes endophthalmitis.

Intracameral antibiotic agents, on the other hand, by their very nature of application, can counteract inadvertent bacterial contamination during surgery and up to an hour post-surgery. However, they obviously have no efficacy on the ocular surface following surgery. The first report of successful antibiotic prophylaxis by injection into the anterior chamber was published in the 1970s.⁵ Additionally, a number of retrospective studies have suggested that intracameral antibiotics can significantly reduce the risk of infection.⁶

The ESCRS performed a prospective multicenter trial of postoperative endophthalmitis after cataract surgery⁷ and reported a rate of 0.07% of presumed infectious endophthalmitis after intracameral cefuroxime treatment vs. a rate of 0.34% in control groups. At first blush, the fivefold reduction in endophthalmitis appears shockingly effective; however, on closer examination, the cefuroxime group had an incidence of endophthalmitis of 1:1,370, which is a similar or even higher rate than that of many contemporary surgeons who use topical antibiotics. What is more surprising is the 1:300 incidence of endophthalmitis for the control group.

Even in the age of large-incision, extracapsular cataract surgery, topical antibiotic use and proper surgical technique has been reported to create an extremely low rate of endophthalmitis — 1:6000. García-Sáenz et al. report an infectious endophthalmitis rate of 0.043% from October 2005 to December 2008 with intracameral cefuroxime compared with a rate of 0.59% without cefuroxime, confirming the outcome of the ESCRS multicenter study.⁸ The efficacy of intracameral cefuroxime as a prophylactic measure against infectious endophthalmitis is well established. Yet why have surgeons had a slow conversion, if this is the case?

Cefuroxime Characteristics

Cefuroxime is a second-generation cephalosporin developed from compounds first isolated from cultures of Cephalosporium acremonium from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu.⁹ It exerts antibacterial activity by inhibition of bacterial cell wall synthesis in susceptible species. Cefuroxime is not a perfect prophylactic because of limited efficacy against gram-negative bacteria. Furthermore, and of more concern, is the drug's high rate of resistance; for example, it will not cover any methicillinresistant Staphylococcus species — Staph. epi. and Staph. aureus are the two most common pathogens, accounting for up to 70% of postop infections. Cefuroxime is not available in a prepackaged form for intracameral use; it has to be diluted from concentrate in the operating room, giving scope for errors in dilution and contamination.¹⁰

In the ESCRS multicenter study, in the proven infective endophthalmitis cases, the absence of cefuroxime and the use of silicone intraocular lens optic material and clear corneal incisions were significantly associated with an increased risk. Further, there was evidence that men were more predisposed than women to infection. The absence of an intracameral cefuroxime prophylactic regimen at 1.0 mg in 0.1 mL normal saline was associated with a 4.92-fold increase in the risk of total postoperative endophthalmitis.

A severe anaphylactic reaction has been reported five minutes after 1.0 mg of cefuroxime was injected into the anterior chamber after routine phacoemulsification and IOL implantation.¹¹ The patient, who had a known allergy to penicillin, recovered well after immediate resuscitative action was taken, emphasizing the need for immediate availability of trained resuscitation staff in the operating room. Reportedly, immunoglobulin E-mediated allergy to cefuroxime occurs in the general population at a rate of 1:1000. Rare though that may be, this is a similar rate to post-cataract surgery infection — and per the ESCRS study, more common than endophthalmitis when cefuroxime is used.

Therefore, the solution we have to this problem includes an adverse event that occurs at an even higher rate. This event can even result in death — the ultimate surgical complication! Furthermore, it is commonplace for those patients allergic to cephalosporins, and even the upwards of 20% of the population allergic to penicillin, to avoid these classes of antibiotic; what is to be done for these sensitive patients?

Intracameral cefuroxime 1.0 mg appears safe in terms of local toxicity; however, one study showed possible endothelial effects in those patients at risk with vulnerable endothelial cells. Dilutional errors have been reported to cause significant adverse reactions after uncomplicated cataract surgery. Cefuroxime achieves high aqueous concentrations even one hour after surgery.¹⁰ However, this generally lasts less than two hours since the turnover of the aqueous humor in the anterior chamber is 1% per minute; therefore, after 100 minutes, all of the aqueous has been replaced.

The Thickening Issue

Regarding the issue of macular thickening linked to cefuroxime, research shows mixed results. In a study of foveal and perifoveal thickness measured by optical coherence tomography after phacoemulsification and IOL implantation, the initial (preoperative) mean value of 234.1 + 2.6 (SEM) (n = 536) in the 6.0-mm perifoveal region increased to 242.5 + 2.6 mm (n = 488) (P<.01) at one week, 247.7 + 4.6 mm (n = 352) (P<.01) at one month, and 246.0 + 5.9 mm (n = 208) (P<.05) at two months. However, the relative change in macular thickness was moderate at 3.5%, 5.6% and 5.3%, respectively. There was no reported correlation between macular thickening and visual acuity.^12,13

Cefuroxime 1.0 mg intracameral use in a double-masked clinical study showed no significant difference in postoperative macular thickness.¹⁴ However, cases of dilutional errors have resulted in macular thickening, chronic CME, serous retinal detachment and even macular infarction.

Cost Considerations

In a recently reported study, Sharifi et al.¹⁵ concluded that, owing to their high costs, the many commonly used topical antibiotic agents are not cost effective when compared with intracameral cefuroxime, even under optimistic assumptions about their efficacy. Efficacy was defined as the absolute reduction in rate of infection from background rate of infection, sourced from the ophthalmic literature. The most expensive topical fluoroquinolones studied, gatifloxacin and moxifloxacin, would have to be more than or equal to 19 times more effective than intracameral cefuroxime to achieve cost-effective equivalence.

The analysis that may need to be done, however, is not a comparison of topical use of fluoroquiolones, but a comparison of intracameral cefuroxime versus intracameral fluoroquinolone. The ESCRS study may therefore hint at the right concept, intracameral delivery, without using the most advantageous agent. The appropriate intracameral drug is broad spectrum, bactericidal, fast acting and nontoxic. Possibly a better antibiotic to use would be a concentration-dependent killing antibiotic such as a fluoroquinolone.

Many studies have shown complete eradication of bacteria within one hour of exposure to fluoroquinolones, improved spectrum of activity and lower allergy and toxicity than cefuroxime. Several reports have shown no intracameral toxicity and possible utility of fluoroquinolones in actual cataract surgery patients; however, similar medical evidence showing efficacy of intracameral fluoroquinolones has not reached the same voluminous level that is presented for cefuroxime. In a straw poll of approximately 50 prominent North American cataract surgeons who use intracameral antibiotics, moxifloxacin seems to have the most proponents, with vancomycin second, followed by either cefuroxime or cefazolin.

Clear corneal incision infection and endophthalmitis.

After ESCRS

The ESCRS endophthalmitis study published preliminary results in 2006¹⁶ showed a near fivefold decrease in the rates of postoperative endophthalmitis with the use of intracameral cefuroxime. The findings generated considerable controversy and, one year later, its recommendations had been heeded by only 6% of ASCRS members.¹⁷ A survey in the United Kingdom sought to gauge the uptake among surgeons there. Fifty-five percent of respondents were using intracameral cefuroxime, with 48% having switched after publication of the ESCRS study. Of those remaining, 68% reported their main concern was the risk for dilution errors in the absence of a commercially preformulated preparation, with 67% stating they would switch if such a product became available.¹⁸

All in ophthalmology are indebted to the ESCRS for conducting this important investigation. Now, the results must be carefully evaluated, and new investigations, where appropriate, should begin. At present, surgeons should compare their own rates of infection with those reported by the ESCRS. Should the surgeon's experience be favorable, perhaps no change in prophylaxis is needed. If the surgeon's rates are high, however, then careful attention to all aspects of infection's prevention is warranted, including the potential use of intracameral antibiotics. OM

References

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16. Barry P, Seal DV, Gettinby G, Lees F, Peterson M, Revie CW. ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery; preliminary report of principal results from a European multicenter study; the ESCRS Endophthalmitis Study Group. J Cataract Refract Surg. 2006;32:407-410.
17. Chang DF, Braga-Mele R, Mamalis N, Masket S, Miller KM, Nichamin LD, Packard RB, Packer M. Prophylaxis of postoperative endophthalmitis after cataract surgery: results of the 2007 ASCRS member survey; the ASCRS Cataract Clinical Committee. J Cataract Refract Surg. 2007;33:1801-1805.
18. Gore DM, Angunawela RI, Little BC. United Kingdom survey of antibiotic prophylaxis practice after publication of the ESCRS Endophthalmitis Study. J Cataract Refract Surg. 2009;35:770-773.

Francis S. Mah, MD, is assistant professor of ophthalmology at the University of Pittsburgh, and co-medical director of the Charles T. Campbell Ophthalmic Microbiology Laboratory. Dr. Mah is a consultant for and has received research support from Alcon and Allergan. He can be e-mailed at mahfs@upmd.edu.