6.10Endophthalmitis Prevention

Ayman Naseri and David F. Chang

Core Messages

ßAntibiotic administration and wound construction are important factors in endophthalmitis

prevention.

ßMany factors can affect the antibiotic selection for the prophylaxis of endophthalmitis, includ-

ing efficacy, safety, patient compliance, and cost.

ßRegardless of the wound size and the location, one must be prepared to suture a cataract inci-

sion if it is not sufficiently watertight.

Continuing advances in cataract surgery technique and technology have raised expectations for both patients and surgeons alike. Cataract surgery is expected to be a relatively painless and quick procedure that achieves outstanding visual results within days after the procedure. With excellent outcomes becoming the norm, cases of acute, postoperative endophthalmitis (POE) are particularly devastating. Since even prompt treatment may not prevent significant morbidity and visual loss, much attention has been focused on POE prevention.

Worrisome trends regarding POE rates following cataract surgery have been reported in the past several years, causing ophthalmologists to reconsider both, the method of antibiotic prophylaxis and the safety of the phaco incision. A study of the US Medicare population revealed a surprisingly high rate of endophthalmitis from the years 1994 to 2001 (1). This study also concluded that the rate of infection had increased over the course of this period, which is of even greater concern. From 1998 to 2001, the rate of endophthalmitis was as high as 0.262% with an average of 0.249%, corresponding to approximately 1 in 400 cases. The authors hypothesize that this increase in the rate of POE may be related to the adoption of sutureless, clear corneal incisions. However, a close look at the data from that study

A. Naseri

Department of Ophthalmology, University of California,

San Francisco, CA, USA

e-mail: Ayman.Naseri@va.gov

revealed that there was a stepwise increase in the rate of endophthalmitis between the years 1997 and 1998, when the rate increased by 46% from 1.73 to 2.53, with a relative plateau in POE rate from 1998 to 2001 (1).

Taban et al. published a meta-analysis which also suggested that the rate of POE may be increasing. In their systematic review of peer-reviewed English language studies, they documented a disturbingly high rate of POE (2). They determined that the average rate of POE had risen to 0.265% between 2000 and 2003, which also corresponded temporally to the period when sutureless, clear corneal incisions had reached a wider adoption. The relative risk of endophthalmitis in that study was 2.55 times greater for clear corneal incisions compared to that of scleral tunnel wounds. Notably, limbal wounds were also found to be protective against POE when compared to clear corneal incisions. It is not clear if limbal incisions in this study were placed beneath the conjunctival insertion, or if they were a variant in the construction of clear corneal incisions with a more posterior external wound. It is also not clear as to how often the sutures were used in each group.

Other researchers did not report any statistically significant increase in the rate of endophthalmitis over the same time period at their institutions (3–6). These reports specifically did not find a statistical link between clear corneal incisions and POE. Instead, some of these studies suggested that the route of antibiotic administration may be one of the most important factors in preventing POE. Incision size may be another potential risk factor. By minimizing the incision size, surgeons may be able to decrease the risk of bacterial contamination and POE.

Because of the concern over the increasing rates of POE, we will review two major factors in the risk of infection: antibiotic prophylaxis and wound construction.

6.10.1 Antibiotic Prophylaxis

There are several potential routes of antibiotic administration for the prophylaxis of POE. Instead of systemic routes, ophthalmologists are able to employ topical, subconjunctival, and intracameral methods of antibiotic delivery to the surgical site. Because of the low rate of surgical infection, it is difficult to conduct prospective, randomized trials that are large enough to prove the efficacy of any method.

Table 6.7 Use of prophylactic antibiotics reported by 1,312 respondents from the 2007 ASCRS Endophthalmitis Survey [26]

This problem is certainly true with respect to using topical antibiotics for the prevention of POE (7). Nonetheless, this method of prophylaxis is universally used in the US. In a recent survey of members of the American Society of Cataract and Refractive Surgery (ASCRS), 91% of respondents stated that they used topical antibiotics perioperatively, while 98% used topical antibiotics postoperatively (Table 6.7) (8). 93% of those using perioperative topical antibiotics employed fluoroquinolones, with 81% using either gatifloxacin or moxifloxacin. Methods of prophylaxis in other countries may be quite different. In a survey of the ophthalmologists in the United Kingdom conducted in 2008, subconjunctival and intracameral cefuroxime were used predominantly, while the most common topical preparation was a combination steroid/neomycin drop (9). It should be noted that neither gatifloxacin nor moxifloxacin are available in the United Kingdom.

The rationale for using topical antibiotics is supported by several types of indirect evidence, including studies of experimental endophthalmitis, measurements of aqueous penetration of topical antibiotics, consideration of the spectrum of anti-bacterial activity, and clinical experience (10–15). To our knowledge, there is only one large retrospective clinical study reporting the rate of endophthalmitis, while using the latest generation fluoroquinolones preferred by most of the respondents who took the ASCRS survey in 2007 (16). Unfortunately, that study was designed to exclude any patient that had an intraoperative complication or a wound leak either before or after the surgery. Since these two exclusion criteria are known risk factors for the development of POE, and since they cannot be predicted preoperatively, this study does not adequately address the efficacy of the latest generation topical fluoroquinolones. Therefore, despite their widespread popularity, the efficacy or superiority of gatifloxacin or moxifloxacin over other agents in the prophylaxis of POE has not been proven.

Subconjunctival injection is another common route of antibiotic administration, although only 13% of the respondents employed this method in the ASCRS survey conducted in 2007 (Table 6.8) (8). This suggests that the use subconjunctival antibiotics has decreased since 1996, when they were used by 46% of ASCRS members surveyed, and this trend could be explained by the shift to topical anesthesia (17). Although there are no prospective, randomized studies to support the use of subconjunctival antibiotics, there is some peer-reviewed clinical evidence suggesting its efficacy in preventing POE. In a study of Canadian patients, Colleaux et al. found that the rate of POE was significantly lower in patients receiving subconjunctival antibiotics (0.011 vs. 0.179%, p = 0.009) (18). Notably, this study did not find a statistically significant association of POE with clear corneal incisions. A second retrospective study from the UK also found that subconjunctival antibiotics were of statistical benefit in the prevention of POE (19).

Finally, in their large, retrospective case control study, Ng and et al. also found that subconjunctival antibiotics and preoperative antisepsis were associated with a significant reduction in the risk of POE (6). Because most of the surgeons used topical antibiotics and did not use intracameral antibiotics, there was insufficient statistical power to assess the benefit of either of these methods of antibiotic prophylaxis. In the same study, however, clear corneal wounds were not associated with an increased risk of POE compared to other wound types.

Although the direct intracameral injection of antibiotics for the prevention of POE has recently become a frequent and fiercely debated topic, the clinical evidence supporting its use dates back to over three decades. During cataract surgery camps in South India

Table 6.8 Preferred routes of antibiotic prophylaxis immediately following surgery as per 2007 ASCRS Endophthalmitis Survey [26]

Percentages total more than 100 because respondents could indicate multiple methods

from 1961 to 1975, Peyman et al. demonstrated a reduction in the rate of endophthalmitis from 3.6 to 0.37%, in a study of over 50,000 patients (20). In the era of large incisions and intracapsular cataract surgery, this remarkable result was achieved with a direct prophylactic intracameral injection of gentamicin. In the phacoemulsification era, Gimbel et al. reported their early experience with intracameral gentamicin and vancomycin. They did not find any case of endophthalmitis in 11,748 patients, which is suggestive of the relative safety of their technique as reflected by the endothelial cell counts (21).

More recent studies have focused on the use of intracameral cephalosporins. In the year 2002, Montan et al. reported the early Swedish experience with direct intracameral cefuroxime injections (22). In their retrospective study of over 32,000 cases, they discovered an endophthalmitis rate of 0.06%, which was significantly lower that the US published rates over a similar period. Of the 13 cases of culture-positive endophthalmitis, 12 infections occurred from organisms resistant to cefuroxime, suggesting that the intracameral route of administration was highly effective against organisms sensitive to cefuroxime (12).

The use of intracameral cephalosporins as prophylaxis against POE has not been limited to cefuroxime. In two retrospective studies from Spain, patients who received an intracameral injection of cefazolin had more than a tenfold lower rate of endophthalmitis than those that did not receive intracameral antibiotics (23, 24). In each of those reports, the rate of endophthalmitis was determined in one group of patients that received intracameral cefazolin, and in another group that did not. In each study, there was more than a tenfold reduction in the rate of endophthalmitis in the group that received intracameral cefazolin.

More recently in a prospective study conducted in Sweden, the outcomes of more than 225,000 cataract extractions, in which patients received an intracameral injection of cefuroxime, revealed an endophthalmitis rate of less than 0.05% (25). Remarkably, this was achieved despite the fact that less than 10% of the patients in that study received any topical antibiotics whatsoever. The strongest evidence of the efficacy of intracameral cephalosporin injections was the prospective, randomized, multi-center trial on the prophylaxis of POE by the European Society of Cataract and Refractive Surgery Surgeons (ESCRS) (26). Although that study was designed for the intended recruitment of 32,000 patients,

the study management team and the data monitoring committee (DMC) determined that the study should be unmasked when approximately half that number had been enrolled. At that time the DMC “advised that it would be unethical to withhold the use of prophylactic intracameral cefuroxime from the two groups who did not receive it.” The rates of culture proven endophthalmitis in the two groups that did not receive intracameral cefuroxime injections were 0.226 and 0.176%, compared to that of 0.050 and 0.025% in the two groups that did receive intracameral cefuroxime. Because endophthalmitis caused by Streptococcus species often leads to severe visual loss (27), it is important to note that there was no Streptococcal endophthalmitis in the two groups receiving intracameral cefuroxime injections (26).

The ASCRS survey conducted in 2007 showed that despite the conclusions of the ESCRS prospective, randomized study, 77% of the respondents were still not using a direct intracameral injection of the antibiotic for prophylaxis (Table 6.8) (8). There are two likely reasons for this outcome, though they are only speculations. First, unavailability of commercial antibiotic preparation that is approved for intraocular use, and fear of risk of using intracameral injections. Forty five percent of those not using intracameral injections were concerned about the risk. Eighty two percent indicated that they might use an intracameral antibiotic injection if it were commercially available at a reasonable cost. Second, the ESCRS study control group did not reflect the most common topical antibiotic regimens, in which most respondents were using topical gatifloxacin or moxifloxacin (81%), and starting topical prophylaxis at least 1 day preoperatively (78%) and immediately postoperatively (66%). Therefore, the ESCRS study did not address whether intracameral cefuroxime was equal to, superior to, or of adjunctive benefit to the most commonly used topical antibiotic protocols.

The ideal antibiotic for direct intracameral injection is not known. Some authors have suggested that if intracameral antibiotics are to be used, latest generation fluoroquinolones may be a better choice. Although there is some preliminary data supporting the safety of intracameral injection of this class of antibiotics (28–30), the clinical efficacy of these antibiotics are yet to be determined in large clinical studies. The majority of large clinical studies advocate the use of cefuroxime intracamerally, but the intracameral injection of cefazolin, vancomycin, and gentamicin has also been reported. Montan et al. studied the safety and pharmacokinetics

Table 6.9 Antibiotics preferred by those using an intracameral route (direct injection or placement in the irrigating bottle) from the 2007 ASCRS Endophthalmitis Survey [26]

of intracameral cefuroxime (31), while Gimbel et al. published their experience with intracameral vancomycin (21). Finally, Murphy et al. used serial aqueous taps postoperatively to show that a single intracameral injection of 0.1 mg vancomycin still provided an aqueous level that was four times the minimum inhibitory concentration (MIC) for most gram positive bacteria, 26 h later (32). Table 6.9 shows the preferred antibiotic choices for intracameral injection among ASCRS members surveyed in 2007 (8).

In summary, the majority of peer-reviewed clinical evidence, both retrospective and prospective, seems to support the prophylactic efficacy of an intracameral level of antibiotic, although the ideal agent is not known. While the evidence of efficacy is the strongest for a direct intracameral antibiotic injection (33), there are also retrospective clinical studies supporting the use of subconjunctival antibiotics, which presumably also achieve an intracameral level of a drug. Although there is no direct evidence that topical antibiotics are efficacious, the improved intracameral penetration of newer generation topical fluoroquinolones at least provides some rationale for their popularity and use (7).

6.10.2 Wound Construction

Modern phacoemulsification incisions also play an important role in the prevention of POE. Regardless of the incision type, any postoperative wound leak would increase the risk of endophthalmitis. In fact, Wallin et al. found that a wound leak on postoperative day one was associated with a 44-fold increase in the risk of POE (34). Most of the debate about wound construction has centered on the relative risk of scleral tunnel vs. sutureless clear corneal incisions. In their prospective randomized study of over 12,000 cataract surgeries, Nagaki et al. found an increased risk of POE in patients who had temporal corneal incisions (35). The findings of this study

supported the observations found in other retrospective, case–control studies (36, 37). Taban et al. further postulated that the overall increase in the rate of POE observed since 1992 is related to the introduction and the adoption of clear corneal incisions (2).

Several studies have offered a hypothesis to determine the role of clear corneal incisions in increasing the risk of POE. These studies have suggested that postoperative fluctuation in intraocular pressure or external manipulation could lead to wound gaping and inflow of surface fluid into the anterior chamber. In a laboratory model using human globes, four of seven eyes demonstrated ingress of India ink into the eye through 3 mm clear corneal incisions (38). The ingress of blood-tinged tear fluid has also been observed in a clinical study of eight patients, when a cannula was used to apply external pressure to the posterior side of clear corneal incisions (39). Other studies have suggested that postoperative fluctuation in intraocular pressure and hypotony may lead to wound incompetence and ingress of extraocular surface fluid, although stepped incisions may be more resistant to this phenomenon (40–42).

An important consideration, however, is the significant variability in how clear corneal incisions are constructed. These wounds can vary in width, radial length, depth, location, angle, anterior and posterior thicknesses, shape, and entry point. There is also variance in the types of blades used for wound construction. Even if surgeons could consistently produce the same incision architecture every time, other variables, such as wound manipulation during cataract surgery can vary. Most of the large retrospective studies that have implicated clear corneal incisions as a risk factor for endophthalmitis have not characterized or commented on their architecture.

Increased scrutiny of clear corneal incisions has allowed some surgeons to identify the features that may influence the risk of endophthalmitis. Investigators from the Bascom Palmer Eye Institute in Miami observed that 86% of the cases of POE at their institution occurred in right eyes with incisions located inferotemporally (8). One hypothesis might be that wounds in this location are in closer proximity to the inferior lid margin and tear meniscus. Others suggested that the shape of the incision is more important to its self-sealing properties. They suggested that square incisions are superior to rectangular ones, because the former are more stable and therefore resistant to early postoperative hypotony and leakage (43). Tam et al. reported