Rationale Behind Antimicrobial Prophylaxis in Ocular Surgery

Terrence P. O'Brien, MD

Endophthalmitis is a rare but devastating complication of cataract surgery that can lead to complete loss of vision. Care must be taken to address all risk factors for endophthalmitis in the preoperative, intraoperative, and postoperative stages of treatment.

Incidence of Endophthalmitis after Cataract Surgery

The incidence of endophthalmitis has been reported to be between 0.03% and 0.14%.^1-4 Whether the incidence of this complication is rising or not is still a subject of debate. Some studies have shown that the incidence has been stable or decreasing over the last 14 years. For example, a retrospective study at Bascom Palmer showed a decrease in postoperative endophthalmitis from 1984 to 2008 and that the average incidence over that 25-year time period was 0.03%.⁴

Other studies have shown that the incidence of postoperative acute endophthalmitis is increasing. The incidence of endophthalmitis after cataract surgery increased in the Medicare population between 1994 and 2001.⁵ During this time period, 500,000 cataract surgeries were performed on this population. From 1998 to 2001 the relative risk (RR) for endophthalmitis was significantly higher than the previous 4 years (RR, 1.41; 95% CI, 1.24-1.60). No hypothesis was given for this apparent rise in the risk of postoperative endophthalmitis.

In a systemic review of 215 studies performed between 1992 and 2003, linear regression was used to show that while the incidence of endophthalmitis after cataract surgery decreased from 1963 to 1991, it has increased from 1992 through 2003. This change was attributed to the advent of sutureless clear corneal incisions. Between 1992 and 2003, the incidence of endophthalmitis with a limbal incision was 0.062%, with a scleral incision 0.074%, and with a clear corneal incision 0.189%.⁶ Other studies also support the idea that clear corneal incisions, with or without sutures, increases the likelihood of acute postoperative endophthalmitis.^7-11

Risk Factors for Postoperative Endophthalmitis

Treating endophthalmitis has become more difficult due to increased antibiotic resistance. All care should, therefore, be taken to prevent it by addressing the risk factors that lead to endophthalmitis. Studies have identified both preoperative and intraoperative risk factors.

A study conducted at Bascom Palmer Eye Institute between 2000 and 2005 identified risk factors for acute-onset endophthalmitis following cataract surgery. These risk factors include systemic immunosuppression (ie, diabetes mellitus) and chronic external diseases such as blepharitis. Also, application of viscous agents such as lidocaine gel can interfere with the effectiveness of povidone-iodine. Perioperative factors (eg, presence of surface bacteria) and intraoperative complications (eg, vitreous loss) also increase the risk of endophthalmitis. The European Society of Cataract and Refractive Surgeons Study Group (ESCRS) concluded that the incidence of endophthalmitis was 5.88-fold higher in patients with a clear corneal incision vs. a scleral tunnel, 3.13-fold higher in patients with a silicone IOL vs. an acrylic IOL, and 4.95-fold higher in patients with surgical complications.¹² Not using an eye patch has also been implicated in increasing the risk of endophthalmitis. Patients may rub their eyes and allow bacteria to enter. Wound leaks and inferior wound location also increase the risk of endophthalmitis. Systemic immunosuppression is a risk factor for infection in any surgery and cannot be controlled by the ophthalmologist. All other risk factors can be addressed by the ocular surgeon.

Role of Patients’ Flora in Endophthalmitis

Studies have shown the infecting organisms of postoperative endophthalmitis were genetically indistinguishable from the patients’ own periocular flora in 82% (14/17) of cases of endophthalmitis.¹³ In 2 cases of Staphylococcus epidermis endophthalmitis, cataract surgery was performed by the same surgeon on the same day. In each case, the isolates coming from each patient were genetically different from each other. The isolates from the aqueous vitreous were also indistinguishable from external isolates in each patient.

Prevention of Postoperative Endophthalmitis

The primary techniques used for preventing postoperative endophthalmitis aim to limit the number of organisms that enter the eye. This goal can be achieved by (1) reducing conjunctival colonization and decreasing the number of organisms on the ocular surface, (2) preventing intraocular bacterial contamination, and importantly, (3) preventing postoperative contamination with watertight wound closure. Eradicating organisms that enter the eye with use of an antibiotic that attains prolonged therapeutic levels in the ocular tissues is also critical in the prevention of postoperative endophthalmitis.

Preoperative preparation

At the time of surgery, proper aseptic technique is strongly supported. The periocular skin should first be treated with a 5% to 10% povidone-iodine scrub and the conjunctiva should be prepared with 5% povidone-iodine solution without irrigating prior to creating the incision. The application of lidocaine gel before the application of the povidone-iodine solution prevents the povidone-iodine from being effective.¹⁴ The antibacterial effect of povidone-iodine was compared to that of silver protein solution in an 11-month study.¹⁵ Topical 5% povidone-iodine was used to prepare the conjunctiva in 1 set of 5 operating rooms, while silver protein solution was used in another set of 5 rooms. In all cases, surgeons continued to use their customary prophylactic antibiotics. A significantly lower incidence of culture-positive endophthalmitis (P <. 03) was observed in the operating rooms using povidone-iodine (0.06%) compared with those using silver protein solution (0.24%) (Table 1). Use of topical povidone-iodine in over 3,000 cases was not associated with any adverse reactions. Antibiotics and povidone-iodine have been shown to be synergistic. In one study, a topical antibiotic and povidone-iodine solution caused a similar and substantial decrease in the number of colonies and species of bacteria isolated in culture. When used together, 83% of the conjunctiva was sterilized.¹⁶ In another study, the combination of fluoroquinolone ophthalmic solution for 3 days plus povidone-iodine solution resulted in a 95% reduction of positive cultures.¹⁷ Based on these observations, the recommendation was made that a broad-spectrum topical antibiotic be given for 3 days preoperatively and that half-strength povidone-iodine solution be used as part of the preoperative preparation to minimize bacterial flora before ocular surgery.

Mechanical measures are also important during the preoperative preparation. Draping the eyelids and eyelashes to sequester the cilia and meibomian glands from the operative field is critical for reducing the risk of endophthalmitis. Meticulous technique in the preparation of the eye prior to initiating the incision is essential in ensuring optimal surgical outcomes.

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Role of the incision in the prevention of endophthalmitis

Although controversy exists regarding whether or not clear corneal incisions increase the risk of endophthalmitis, they have become the preferred incisions of the vast majority of ocular surgeons. In a survey of the members of the American Society of Cataract and Refractive Surgery (ASCRS) conducted in July 2003, 72% of respondents reported using clear corneal incisions. The rate had steadily increased from 1.5% in 1992 to 12.4% in 1995 and to 47% in 2000. Sutureless closure was the preferred technique for 92% of the responding physicians.¹⁸

This preference is understandable given the many advantages of clear corneal incisions. Compared to scleral tunnel incisions, clear corneal incisions reduce surgical time, offer faster postoperative recovery, and lower the rate of induced astigmatism. However, care must be taken to avoid suboptimal incisions that may increase the risk of postoperative endophthalmitis. An improperly constructed wound lacks an adequate length of corneal tunnel. A wound that is not square is also considered improperly constructed. These substandard incisions lack the self-sealing properties of a sufficiently constructed wound. Incisions in the inferior aspect of the temporal cornea are also thought to have a higher risk of contamination from organisms and contaminants from the inferior conjunctival fornix.¹⁹ The ideal clear corneal incision is arcuate with a much greater arc than cord length.

Transient postoperative hypotony may lead to wound gaping, allowing fluid from the ocular surface to migrate along the incision and enter the anterior chamber. With the ideal incision, stromal hydration causes the stroma surrounding the incision to swell and forces the roof of the incision down onto its floor—apposition that enhances endothelial pumping, allows for a vacuum seal, and lasts for longer than 24 hours.¹⁹ Stromal hydration of the main incision and all sideport incisions prior to and after testing them with fluorescein can ensure that a watertight seal is achieved. If there is any wound gaping and leakage, the incisions should be closed with a 10-0 polyglactin 910 suture and the knots should be buried to avoid foreign body sensation.

Antibiotic Choice in Endophthalmitis Prophylaxis

Controversy persists regarding the precise role of antibiotics in reducing the risk of endophthalmitis. In a time when multidrug resistance is increasing, obtaining an antibiotic sensitivity profile may be an important step to take before initiation of antibiotic prophylaxis. The gram-positive organisms that usually cause endophthalmitis are increasingly resistant to even newer fluoroquinolones.²⁰ There have also been cases where newer fluoroquinolones were applied perioperatively and infection still occurred. For example, in a case of endophthalmitis cause by S epidermis, the organism recovered was methicillin-resistant and newer fluoroquinolone-resistant. The organism was, however, susceptible to vancomycin, and visual acuity was able to be preserved. In another case of endophthalmitis caused by methicillin-resistant S aureus (MRSA), the organism was again newer fluoroquinolone-resistant but not vancomycin-resistant. Thus alternatives to fluoroquinolones should be considered, especially if MRSA is a suspected pathogen.

Other alternative antibiotics include trimethoprim, bacitracin, minocycline, sulfamethoxazole, and tobramycin. These agents also have the advantage of being less expensive than vancomycin and the fluoroquinolones.

Besifloxacin is a newer fluoroquinolone that has been developed specifically for ophthalmic use and not systemic use, which may decrease the likelihood of resistance. In besifloxacin, the methoxy group at the eighth position is replaced with a chlorine molecule. Attached to the carbon at the seventh position is a bulky side chain that enhances the potency of besifloxacin. In vitro testing has shown that it has a lower minimum inhibitory concentration against gram-positive pathogens than that of 8 methoxy-fluoroquinolones like moxifloxacin.²¹

Because in vitro resistance to fluoroquinolones develops via multi-step mutations,²¹ potent inhibition of both enzymes necessary for bacterial replication and survival (DNA gyrase and topoisomerase IV) decreases the rate of resistance. Balanced activity against each enzyme is desirable to minimize the rate of antibiotic resistance. Studies have shown that compared to other fluoroquinolones, besifloxacin displays more balanced targeting in Escherichia coli and Streptococcus pneumoniae (Table 2).²²

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Besifloxacin has a unique vehicle, a polycarbophil suspension matrix that delivers drug to the ocular surface and allows it to remain on the ocular surface. High concentrations of besifloxacin have been achieved on the ocular surface, the preocular tear film, lids, and lashes, where the organisms reside.

In a study of 108 patients in 3 study groups, conjunctival biopsies were taken at 15 minutes, 30 minutes, 2 hours, 6 hours, 12 hours, or 24 hours after dosing with one of 3 antibiotics—gatifloxacin (0.3% solution), moxifloxacin (0.5% solution) or besifloxacin (0.6% suspension). The maximum mean concentration (C_max) occurred at 15 minutes for all 3 compounds. The C_max for moxifloxacin (10.7 µg/g) was more than double that of gatifloxacin (4.03 µg/g) and besifloxacin (2.30 µg/g). Whereas concentrations at 30 minutes for moxifloxacin and gatifloxacin were approximately one-half those of the respective 15 minute time-points, the mean concentration of besifloxacin remained stable between 15 minutes and 30 minutes.²³

For all 3 fluoroquinolones, the mean concentrations declined with each successive time-point. At 24 hours post-instillation, the mean concentrations were 0.034 ± 0.026 µg/g for besifloxacin, 0.025±0.031 µg/g for moxifloxacin, and 0.019 ±0.013 µg/g for gatifloxacin. The besifloxacin group had the greatest number of subjects with quantifiable amounts of drug in the tissue at 24 hours (4/6), compared with the gatifloxacin group (3/6 subjects) and the moxifloxacin group (2/6 subjects). Besifloxacin also had the greatest area-under-the-curve (AUC) to MIC₉₀ ratio.²³

Intraoperative Antibiotic Prophylaxis

Even with meticulous preoperative preparation, there still may be rare instances where organisms enter the eye. Therefore, surgeons must be aware of effective strategies to eradicate the pathogens that do enter the eye during surgery.

Results of the ESCRS study on endophthalmitis strongly support the use of intracameral antibiotics during cataract surgery.²⁴ The ESCRS study included 24 ophthalmology units and eye clinics in Austria, Belgium, Germany, Italy, Poland, Portugal, Spain, Turkey, and the United Kingdom. This study included a total of 14,000 patients, divided into 4 study groups. Thirteen of the 3,438 patients (0.004%) in the group that received no intracameral antibiotics developed endophthalmitis (Table 3). Three of the 3,408 patients (0.0009%) who received intracameral cefuroxime developed endophthalmitis. Ten of the 3,424 patients (0.03%) that only received perioperative levofloxacin developed endophthalmitis. Two of the 3,428 patients (0.0006%) who received intracameral cefuroxime and perioperative levofloxacin developed endophthalmitis. In the 2 groups that received intracameral cefuroxime, only 5 of the 6,836 patients (0.07%) developed endophthalmitis while 23 of the 6,862 patients (0.33%) in the groups that received no intracameral cefuroxime developed endophthalmitis. The study was stopped early because it was deemed unethical to not administer intracameral cefuroxime when it had such a clear benefit.²⁴

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Of the 29 patients with clinically-diagnosed endophthalmitis, 14 were diagnosed by polymerase chain reaction (PCR). Streptococcus was isolated in 7 cases of endophthalmitis. While 100% of streptococcus isolates were sensitive to vancomycin and levofloxacin, only 4 of 6 isolates (66.7%) were sensitive to cefuroxime (Table 4). Of the coagulase-negative Staphylococcus (CoNS) isolates, only 33.3% were susceptible to cefuroxime. However, similar to streptococcus isolates, all CoNS isolates were susceptible to vancomycin and levofloxacin (Table 4).

These results indicate that cefuroxime was not the ideal agent to use against staphylococcus or streptococcus. Resistance to it was high. In addition, the cefuroxime was reconstituted from powder and the resultant mixture had only short-term stability. Potential for contamination during reconstitution makes this powder less than ideal for an intracameral injection. Intracameral injection with cefuroxime also carries a risk of â-lactam hypersensitivity.

Any intracameral injection of an antibiotic carries risks. Errors related to mixing, concentration, and buffering can cause toxic anterior segment syndrome (TASS). In addition, the use of intracameral vancomycin had been implicated in some cases of cystoid macular edema. Intracameral antibiotics can also cause endothelial cell loss and toxicity and aminoglycosides can be toxic to the retina.²⁴ These risks may explain why 77% of respondents to the 2007 ASCRS survey were still not using intracameral antibiotics. However, 82% of respondents indicated that they would likely use a commercially available, FDA- approved preparation. ²⁵

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Postoperative Antibiotic Prophylaxis

While controversial, evidence supports postoperative administration of topical antibiotics. In a retrospective, observational case series including 20,013 patients from 9 cataract surgery units in 7 states, 16,209 patients (81%) received postoperative topical gatifloxacin and 3,804 patients (19%) received postoperative topical moxifloxacin for prophylaxis against endophthalmitis.A total of 14 patients (0.07%) developed endophthalmitis—9 patients in the gatifloxacin group and 5 patients in the moxifloxacin group. The difference between the groups was not statistically significant. In the 10 culture-positive cases, CoNS was most common, followed by streptococci.³

More importantly, 6 cases of endophthalmitis occurred after the drops were stopped at 7 days and all but one case developed within 9 days of surgery. The case that occurred 22 days postoperatively was attributed to wound leakage.³

In summary, physicians must be aware of strategies to reduce the risk of postoperative endophthalmitis. Meticulous surgical technique and proper wound construction is important. The use of povidone-iodine and proper draping of the lids and lashes is also critical. Surgeons should also consider the use of antibiotics. These steps will reduce the risk of postoperative endophthalmitis, leading to improved surgical outcomes and satisfied patients.

References

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