As all practitioners know, endophthalmitis is a devastating complication of ophthalmic surgery. Fortunately, it occurs at a relatively low rate.^1-5 Over the decades, several factors have influenced the occurrence of endophthalmitis: outpatient vs. inpatient procedures, hospital-based operations vs. ambulatory care facilities, injected vs. topical anesthesia, self-sealing clear corneal incision vs. sutured incision site, modification in intraocular lens design and materials, changes in antibiotic prophylaxis and the sensitivity of organisms to the available topical antibiotics.^1-5

Because of these changes, postoperative infection rates have been contained, if not decreased. The new generation topical antibiotics impact on the incidence of postoperative infection has been significant and beneficial for both patients and surgeons.

Defining Endophthalmitis
Endogenous or exogenous endophthalmitis is defined as inflammation of the internal ocular spaces secondary to intraocular infection.^1-13

• Endogenous. The much less common endogenous variety—also termed metastatic endophthalmitis—occurs when organisms circulate through blood-borne pathways and enter the internal ocular spaces through the blood-ocular barrier.^6-8 Medical conditions, such as diabetes mellitus, liver disease, cardiac disease and malignancy, as well as the presence of an indwelling catheter and intravenous drug use are sources of endogenous endophthalmitis.^6-9

• Exogenous. Infectious exogenous postoperative endophthalmitis results when normal conjunctival flora becomes introduced into the eye from external sources such as contaminated instruments, disposable supplies, prepared solutions, the surgical field or intraocular lenses.^10-13 Exogenous endophthalmitis may be acute, chronic or delayed in onset. Additional mechanisms include penetrating ocular trauma, intraocular foreign bodies, corneal ulceration and breach of ocular barriers from a periocular infection.^10-13

Most cases of endophthalmitis are acute, occurring within one to two weeks following surgery.² The classic patient presentation includes pain, redness, reduced visual acuity, complaints of floaters and photophobia.^2,14 While these symptoms may be present to some degree as part of the normal postoperative course, if they worsen or fail to resolve with standard therapies, immediate evaluation to rule out infection is required.^2,14

What Causes Endophthalmitis?
Two noteworthy events have influenced modern cataract surgery and perioperative management: in 1992, the clear corneal incision (CCI) approach was popularized, and in 2003, the fourth-generation topical fluoroquinolones entered the market.^5-9 These two factors continue to receive the greatest attention in the literature with regard to rates and causes of endophthalmitis.^4-6

Mehyray Taban, M.D., and colleagues investigated the rate of postoperative endophthalmitis.¹ The overall rate of postoperative endophthalmitis in their study was 0.128% with an increasing incidence over time.¹ This increase was significant and seemed to coincide with the development of the sutureless clear corneal approach.^1,15,16

Decreased wound stability likely accounts for the documented increased frequency of post-cataract endophthalmitis following CCI.¹ Defects such as wound gape, wound-edge malposition and wound leakage have been associated with up to 80% of postsurgical endophthalmitis.^17,18 Squeezing of the lids or excessive unconscious blinking secondary to the discomfort caused by the procedure induces posterior movement of the globe. This contributes to increased eyelid-to-wound exposure and IOP fluctuations, which have the potential to cause gaping of the unhealed corneal wound margin.¹⁹

Wound gape provides the potential for organisms to migrate from the ocular surface into the cornea.^19,20 Unlike procedures using scleral tunnel incisions, clear corneal procedures are left unprotected to the environment with no conjunctival cover.^21-23 However, other studies have failed to identify an increased rate of endophthalmitis when comparing scleral tunnel incision to CCI.^3,23 In these reports, the method of antibacterial prophylaxis was considered to be the more important determinant in the likelihood of postoperative infection.^3,23

The Latest Treatment
In the spring of 2003, the latest generation of topical ophthalmic antibiotics—the fourth-generation fluoroquinolones—were approved in the United States.^24-26 The American Society of Cataract and Refractive Surgery (ASCRS) 2003 Survey of Practice Styles and Preferences recorded an immediate endorsement of the antimicrobial agents: 61% of respondents preferred the use of the fourth-generation preparations Zymar (gatifloxacin 0.3%, Allergan) or Vigamox (moxifloxacin 0.5%) to all other topical antibiotics, while Quixin (levofloxacin 0.5%, Vistakon) was preferred by 9% of respondents.¹⁶ These new-generation medications have solidified themselves as the most commonly used anti-infective agents in the perioperative management of cataract surgery, even though their use is off-label.²⁶

By 2007, 91% of ASCRS members surveyed reported using topical antibacterials perioperatively and 98% used the agents postoperatively.²⁷ U.S. respondents to the survey used fluoroquinolones in 93% of cases—81% using either gatifloxacin or moxifloxacin.²⁷ Practitioners believed that, perioperatively, the medication can sterilize the ocular surface to limit the chance of bacterial entry at the time of surgery and that the medications obtained therapeutic antibiotic intraocular concentrations via topical application.²

Fourth-generation fluoroquinolones include moxifloxacin, gatifloxacin and the newest agent, Besivance (besifloxacin, Bausch + Lomb). They work in two ways: by targeting both bacterial topoisomerase IV and DNA gyrase leading to cell death to make them bactericidal and by disabling the agent ejection system.^26-30 These medications have gained acceptance in the clinical community for their penetration, broad-spectrum antimicrobiological activity, minimal toxicity to ocular tissues and low potential for bacterial resistance.^26-30

Several studies have compared the coverage and penetration of the generations of fluoroquinolones.^31,32 These reports suggest that the new medications have broader coverage and deeper penetration into ocular tissue.^31,32 Studies assessing corneal penetration have found that, among the fourth-generation fluoroquinolones, higher levels of moxifloxacin were found in the aqueous humor after topical administration; other studies suggest that gatifloxacin may eradicate bacteria more quickly.^31,32

An in vitro study compared the susceptibility patterns and minimum inhibitory concentration potencies of moxifloxacin and gatifloxacin with the earlier-generation fluoroquinolones.²⁸ The study included 93 isolates of bacterial endophthalmitis and revealed that the fourth-generation agents covered bacterial resistance more efficaciously, compared with second- and third-generation fluoroquinolones; fourth-generation agents were more potent against gram-positive bacteria and equally potent for gram-negative bacteria.²⁸

Targeting the Source
In an extensive review by Robert Fintelmann, M.D., gram-positive organisms were identified as the most common source of endophthalmitis after cataract surgery.² These pathogens typically originate from microflora harbored by the patient’s eyelids and conjunctiva; coagulase-negative Staphylococcus (S. epidermidis) is the predominant causative organism.^33,34 Specifically, the gram-positive, coagulase-negative bacteria accounted for 70% of the cases of endophthalmitis in the Endophthalmitis Vitrectomy Study.³⁵ Gram-negative organisms accounted for only 5.9% of culture-proven isolates.³³

When topical fluoroquinolones were introduced in the 1990s, the targeted organisms were considered universally susceptible to the medications.³⁶ Since then, an increase in resistance has been reported with the highest rates associated with ciprofloxacin, ofloxacin and levofloxacin.³³ Multiple reports have documented up to a three-fold increase in the resistance to ciprofloxacin among gram-positive ocular isolates between 1989 and 2003.^37,38

The ability of the fourth-generation fluoroquinolones to inhibit both DNA gyrase and topoisomerase IV enzymes decreases the likelihood of bacterial resistance. In theory, it is unlikely that bacterial resistance due to spontaneous mutation of both enzymes would occur.^39,40
It is possible to see resistance through a cellular adaptation of a multidrug resistant efflux pump, which permits the cell to pump the unwanted antibiotic agent out of the bacterial cell.^39,40 Fortunately, resistance to the fourth-generation fluoroquinolones remains low.^33-36

The Efficacy of New Agents
Two recent reports demonstrate that resistance to the new topical agents exists.^39,41 A 1996 to 2004 retrospective case review of endophthalmitis caused by S. epidermidis revealed that gatifloxacin and moxifloxacin were not active against 33% of methicillin-resistant Staphylococcus isolates; a report by Darlene Miller, D.H.Sc., and colleagues found increased resistance to gatifloxacin and moxifloxacin among coagulase-negative S. epidermidis isolates.^39,41 While resistant strains naturally will evolve over time, their inception is not likely perpetuated by the use of these topical drugs.

Randomized, prospective studies showing the efficacy of new generation topical antibacterial therapy, in comparison to the old, is lacking. A large clinical outcome study performed by Michael K. Jensen, R.Ph., M.S., and colleagues examined the rate of endophthalmitis with fourth-generation fluoroquinolone use.⁴² This retrospective study included 29,276 cases from 1997 to 2007 and showed a decreased rate of endophthalmitis (0.056%) after the introduction of the new medications.⁴² This compared to a rate of 0.197% in a historical control group of ciprofloxacin and ofloxacin.⁴²

In one of the first clinical outcome studies to examine the effectiveness of the topical fourth-generation fluoroquinolones, Majid Moshirfar, M.D., and colleagues performed a retrospective review of endophthalmitis rates of 20,013 cataract surgeries.⁴³ An overall endophthalmitis rate of 0.07% was reported with the use of moxifloxacin and gatifloxacin.⁴³ It should be noted that their study excluded cases with intraoperative complications or a wound leak.⁴³ Intraoperative complications and wound leak are associated with higher rates of endophthalmitis and may have contributed to an underestimation of endophthalmitis rates.⁴³

Dr. Moshifar’s data was slightly improved over a large case series completed by Ravilla Ravindran, M.D., and colleagues, where the incidence of endophthalmitis was reported at a rate of 0.09% following cataract surgery employing topical ciprofloxacin.⁴⁴

Introducing New Formulations
New medications and changes in the formulation of existing fluoroquinolones have bolstered the efficacy of this drug class. Receiving U.S. approval in 2009, Besivance is the most recent fourth-generation fluoroquinolone to be approved for ophthalmic use.⁴⁵ Its unique formulation includes the polycarbophilic mucoadhesive vehicle DuraSite (Insite Vision), which allows the drug to remain on the cornea and conjunctiva for an increased amount of time.⁴⁵ This increased contact time allows for greater penetration of the medication into the aqueous humor and other target tissues, presumably increasing the rate at which bacteria may be eliminated.⁴⁵

The medication is not without some potential disadvantages. Peter J. Ness, M.D., and colleagues investigated DuraSite for potential toxicity to intraocular structures.⁴⁵ Using a population of New Zealand white rabbits, they found that when the compound gains direct access to the anterior chamber in bolus form by way of a clear cornea surgical incision, the chemical has the potential to block the trabecular meshwork, raising intraocular pressure (IOP) and induce toxic effects to anterior segment structures.⁴⁵ The group recommended that when using the preparation postoperatively, if surgical wounds cannot be clearly verified as secure, the surgeon should place a suture over the clear corneal wound to insure its complete closure.⁴⁵

Recent formulation changes of existing medications include increasing the concentration of both gatifloxacin and moxifloxacin. Zymaxid (Allergan), FDA approved on May 18, 2010, increases the concentration of gatifloxacin to 0.5%. Moxeza (Alcon), received FDA approval on November 19, 2010 and is a reformulation of the company’s Vigamox with a new vehicle—xanthan gum—with twice the penetration to support b.i.d. labeling. A clinical study comparing the established concentration of moxifloxacin 0.3% to the new 0.5% formulation demonstrated a 1.8-fold higher peak level of moxifloxacin concentration within conjunctival tissue.²⁹ Increased drug concentration and residence time on the ocular tissues may aid in organism eradication, slowing or preventing resistance.⁴⁶

A Lower Rate of Occurrence
Post-surgical patient compliance plays a critical role in the success of post-procedural medical therapy. Treatment failures occur predominantly when patients fail to adhere to recommended regimens.

The use of intracameral antibiotics—injected into the eye directly during surgery—not only delivers a larger concentration of antibiotic intraocularly, but also has the potential to eliminate the variable of noncompliance.^{2,5,15,18,27,30} A large study conducted by the European Society of Cataract and Refractive Surgeons demonstrated that intracameral injection of the antibiotic cefuroxime reduced the occurrence of endophthalmitis compared to perioperative topical medications alone.³⁰

The widespread use of intracameral antibiotics has not been adopted by U.S. surgeons due to concerns that methacillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas species lack sensitivity to cefuroxime (the intracameral drug-of-choice) and that the medication is not available in a packaged form—it must be mixed as a fortified antibiotic at the time of the procedure.^5,27,46

New trials are investigating the use of “packaged” moxifloxacin, among other agents, in hopes of uncovering medicines with intracameral potential and broad-spectrum coverage that are non-toxic to the eye and cost effective. These investigations hope to offer U.S. surgeons a more viable intracameral option.^33,47

Additional prophylactic regimens exist to reduce rates of endophthalmitis. These include the installation of povidone-iodine 5% solution in the conjunctival sac immediately before surgery, subconjunctival injection of antibacterials, the use of a collagen shield as a mediation reservoir to deliver antibiotic to the ocular theater and antibiotic-bathed intraocular lenses (implants).^2,5,47 Type and route of administration, the spectrum of bacterial coverage, potential adverse medication effects, efficacy, ease of use for the patient, cost, local standards of care and the surgeon’s personal experience all help determine the strategy.²

Two large studies have reported a decrease in endophthalmitis rates following the introduction of the topical fourth-generation fluoroquinolones.^3,42 In the U.S., rates were found to decline following the switch to these medications in 2003 and similar supporting data was seen in Canada in 2004.^3,42 While the data supports what is intrinsically suspected—newer generation antibiotic therapy (perioperative and postoperative) reduces the rates of postprocedural infection—additional large prospective clinical trials need to confirm this hypothesis. 

Dr. Myers is a senior staff optometrist at the Coatesville Veterans Affairs Medical Center in Pennsylvania. He serves as a clinical consultant at The Eye Institute and lectures on anterior segment disease. He participates in the International Master of Science in Clinical Optometry program at The Pennsylvania College of Optometry.

Dr. Gurwood is a professor of clinical sciences, an attending optometric physician in Module 1 of The Eye Institute of the Pennsylvania College of Optometry and part of the clinical staff at Albert Einstein Medical Center.

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