50   Endophthalmitis

Despite the tremendous advancements in the technology and techniques of modern cataract surgery, one of the earliest identified complications continues to plague surgeons. Endophthalmitis is arguably the most devastating vision-threatening complication associated with cataract surgery, and its incidence and prevalence have not changed significantly in 50 years. Surgeons are no closer to eliminating this potentially catastrophic complication now than they were in a half-century ago.¹

Because of the potentially-vision threatening complications of postsurgical endophthalmitis, identifying the risks, refining the methods of infection prophylaxis, and improving treatment have been the subject of ongoing research and debate. Although it is fortunate that postsurgical endophthalmitis is rare, the low incidence makes it difficult to perform prospective clinical trials to definitively determine the causes and the most effective means of preventing postoperative infections. Cataract surgeons must therefore exercise clinical judgment based on the best available published evidence. This chapter discusses the findings in the medical literature, and provides some guidance on current best practices while the research and debate continue.

Incidence and Prevalence

Worldwide, postoperative acute, bacterial endophthalmitis has been reported to occur in 0.04 to 0.2% of cataract surgical cases.¹ Surprisingly, despite reducing complications, making smaller incisions, and reducing surgical times, there appeared to be an increase in the incidence of endophthalmitis reported in the United States at the start of this century.² Using Medicare data, two studies from the same group found similar trends. In 2005, West et al³ reported that the rate of endophthalmitis increased, whereas in the same year Taban et al² reported an increased rate of endophthalmitis associated with clear corneal versus scleral tunnel incisions.

Internationally, the Swedish national reporting database identified an endophthalmitis incidence of 0.05% in over 225,000 cases.⁴ In India, an analysis of over 42,000 consecutive cases, including manual extracapsular and phacoemulsification techniques, found the incidence of postoperative endophthalmitis was 0.09%.⁵ Finally, two studies performed in Canada found similar rates, 0.14% and 0.15%, of endophthalmitis after cataract surgery.^6,7

Etiology

The normal ocular surface is colonized with a spectrum of pathogens that are considered to be a primary source of infection in endophthalmitis.⁸ Conditions altering the normal flora such as contact lens wear, blepharitis, lacrimal system disease, and previous antimicrobial use may increase the risk of postoperative endophthalmitis.^8–10 The normal flora may also be altered in patients who are chronically institutionalized, health care workers, and patients with indwelling catheters or with ileostomies or colostomies.¹¹

Certain pathogens may also vary by geographic region. According to the North American Endophthalmitis Vitrectomy Study (EVS), 94.2% of culture-positive acute, postsurgical endophthalmitis cases involved gram-positive bacteria; 70.0% of these isolates were coagulase-negative Staphylococcus (CoNS), 9.9% were Staphylococcus aureus, 9.0% were Streptococcus species, 2.2% were Enterococcus species, and 5.9% were gram-positive species.¹² In contrast, a survey from India reported that gram-positive bacteria accounted for only 53% of postoperative endophthalmitis cases, whereas 26% were gram-negative isolates and 17% were fungal.¹³ One ominous trend is that evidence suggests that the incidence of methicillin-resistant S. aureus (MRSA) ocular infections is rising, both in total numbers and as a percentage of all S. aureus infections.^14–16 In the EVS, S. aureus was the second most common organism after CoNS. A later longitudinal study by Major et al¹⁶ found that MRSA accounted for 44% of postcataract S. aureus endophthalmitis in one institution from 1995 through 2008, whereas not a single case of MRSA had been identified at the same institution from 1984 through 1992. A significant number of S. aureus cases were resistant not only to methicillin, but also to the commonly used fourth-generation fluoroquinolones, such as moxifloxacin and gatifloxacin. Fortunately, all Staphylococcus species were sensitive to vancomycin, the intravitreal antibiotic of choice to treat gram-positive bacterial infections.¹⁷

Risk Factors

Identifying patients at risk for acute endophthalmitis after cataract surgery is important from both a public health standpoint and a clinical perspective, as this could possibly prevent the occurrence or at least facilitate earlier intervention before the onset of irreversible vision loss. In one published systematic review and meta-analysis, large-incision extracapsular or intracapsular cataract extraction, a clear corneal incision, silicone intraocular lenses, and intraoperative complications such as posterior capsular rupture were strongly and consistently associated with acute endophthalmitis.⁷ All of these factors are easily assessed and do not entail a lengthy medical history or laboratory evaluations. Other significant factors with a lower strength of association in the same meta-analysis were male gender and older age (85 years and older). All of these factors can be measured and monitored in the early postoperative period. The increased risk with age was only true for the older ages (≥ 85 years), and this result might be explained by a reduced natural immunity in this advanced age group.^4,7,18 In addition, a large prospective study identified older patients (≥ 80) as more likely to have normal bacterial flora as well as resistant strains.¹⁹ Several studies have reported increased rates of adverse postsurgical events among men.^7,20 Researchers have noted that men had a 41% increased risk of postoperative endophthalmitis compared with women. Possible explanations for the higher complication rates in men include behavioral differences (e.g., lack of adherence to postoperative instructions and antibiotic use)²¹; differences in bacterial flora between the genders²²; and use of α-antagonists, which can increase the surgical complexity, as there is a clear relationship between these medications and intraoperative floppy iris syndrome.²³

Is a clear corneal incision associated with a greater risk of endophthalmitis compared with a scleral tunnel or limbal incision? Controversy exists regarding this question. Theories to account for more frequent infections with sutureless clear corneal incisions are centered on the stability of the surgical wound because its lack of integrity is believed to be a critical factor. A stable, self-sealing incision may be technically more difficult in the cornea than in the sclera. Many reports concluded that postoperative wound defects were a risk factor for the development of endophthalmitis,^24,25 and a corneal incision at least 2.0 mm in length had substantially greater resistance to incision failure.²⁶ This suggests that the integrity of a self-sealing incision depends to some extent on length. This may be more difficult in a clear corneal incision. If the incision is too short, the cataract wound may be susceptible to a postoperative perturbation (such as rubbing of the eye) and wound abnormality. Two studies showed the rates of adverse events, including endophthalmitis, decreased among patients undergoing small-incision phacoemulsification from 1994 to 2006, due to the innovations in phacoemulsification technology, the types of instruments available to better manage complex cases (pupil stretchers, capsular tension rings, dyes to stain the capsule), increased use of topical anesthesia, improvements in intraocular lenses, changes in preoperative or postoperative medication regimens, and better strategies to deal with intraoperative complications.^7,27 The incision location, structure, and length should be more thoroughly studied in large prospective clinical trials.

Prevention

Operating Room Aseptic Protocols

The combination of povidone-iodine 10% with a detergent remains the compound of choice for effective skin antisepsis. In vitro and in vivo tests show consistent bacterial kill rates of over 99.99%.^28,29 In the event of an iodine allergy, chlorhexidine gluconate is an iodine-free antimicrobial that is as effective as povidone-iodine in bacterial suspension tests, although under practical conditions it may perform slightly less well, and there may also be ocular symptoms and toxicity.³⁰

Practice patterns for the prevention of postoperative endophthalmitis almost universally include preoperative sterile preparation of the surgical site. In most cases, this involves the instillation of povidone–iodine 5% solution into the conjunctival cul-de-sac, a practice of proven efficacy in reducing the bacterial load.^31,32 A prospective study demonstrated that topical antibiotics had no significant additive effect on the preoperative reduction of conjunctival bacterial colonization beyond the effect of povidone–iodine 5% solution alone.³³ A 5% concentration of povidone-iodine is more effective than 1% in decreasing the human conjunctival bacterial flora in vivo.³⁴ There is some evidence that the use of lidocaine gel prior to instillation of povidone–iodine 5% solution diminishes its antimicrobial effect.³⁵ In cases of documented or suspected iodine allergy, polyhexanide³⁶ or chlorhexidine gluconate are recommended as effective alternatives, although some ocular symptoms or toxicity may occur with higher concentrations.

Although bacteria may gain intraocular access during surgery,^37,38 it has been demonstrated that povidone–iodine conjunctival irrigation effectively prevents endophthalmitis.³⁹ An evidence-based assessment of endophthalmitis prophylaxis found that preoperative povidone–iodine antisepsis received the highest rating compared with other preoperative techniques.⁴⁰

Draping and Lashes

Proper draping is critical to ensure that the lashes and lid margins are entirely sequestered by overhanging wraparound flaps from the drape. The potential for microbial contamination from exposed lid margins and lashes is a clear source of pathogens.^41–43

Antimicrobial Agents and Resistance

Unfortunately, the development of antibiotic resistance is universal. Causative factors include the widespread systemic use of antibiotics and the use of antibiotics in agriculture.^44,45 The emergence of resistant bacteria in ophthalmology has been documented in the evaluation of isolates from keratitis and conjunctivitis.^46,47 Although newer fourth-generation fluoroquinolones theoretically have less susceptibility to the development of resistance and an enhanced spectrum of activity against many gram-positive bacteria,⁴⁸ one study found that the majority of MRSA are resistant to ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin.⁴⁹ The rapid evolution of resistant bacteria has amplified the importance of developing newer and more potent ophthalmic antibiotics. Besifloxacin, a new broad-spectrum fluoroquinolone, is the most recently approved for ophthalmic use. A potential advantage of this medication is that it has no systemic, veterinary, or agricultural uses.⁵⁰

Cefuroxime, a second-generation cephalosporin with bactericidal action, was extensively evaluated in Sweden prior to its widespread use following the European Society of Cataract and Refractive Surgeons (ESCRS) Endophthalmitis Study.^51,52 Two gaps in the coverage of cefuroxime are MRSA and multiresistant Enterococci, such as vancomycin-resistant Enterococci. Vancomycin has also been used as an intracameral antibiotic for the prevention of endophthalmitis. Because vancomycin remains one of the last resorts in the treatment of multidrug-resistant bacteria, there has been controversy and historical concern about whether routine intracameral vancomycin administration could contribute to future resistance to the drug.⁵³

Topical Prophylaxis

In addition to preoperative povidone–iodine antisepsis,^53–55 perioperative topical antibiotic prophylaxis is very common in the United States. However, controversy regarding its efficacy remains.^40,56 In the United States, fourth-generation fluoroquinolones have emerged as the most commonly prescribed topical prophylactic therapeutics because of their broad-spectrum activity and superior ocular penetration.^57,58

The optimal timing and frequency of topical antibiotic prophylaxis has also been the subject of debate. Many surgeons begin dosing antibiotics on the day of surgery. However, based on the pharmacokinetics of fluoroquinolones, starting these 1 to 3 days before surgery may be advantageous.⁵⁹ There is evidence that frequent instillation of topical fluoroquinolones immediately before surgery may increase the concentration of drug in the anterior chamber and decrease the bacterial load.^60,61 Preoperative topical antibiotic use reduces the number of bacteria on the ocular surface at the time of surgery; postoperative topical antibiotic use without a taper until the wound is sealed addresses postoperative inoculation.⁶² It is common for antibiotic drops to be discontinued 1 week after surgery, although some studies suggest that the average time of presentation of endophthalmitis is 9.3 days after clear corneal incision cataract surgery.⁵⁸

No prospective study has been conducted to provide direct proof that topical antibiotic use decreases the risk of endophthalmitis. In the ESCRS study, perioperative use of topical levofloxacin was associated with a decreased rate of endophthalmitis, but the benefit did not achieve statistical significance. Further studies are needed to evaluate the ideal drug, dosing, and route to prevent postoperative endophthalmitis.

Intracameral Antibiotic Agents

Of the various methods of antibiotic prophylaxis, the strongest evidence supports a direct intracameral bolus at the conclusion of surgery. Two early and large retrospective studies suggested that direct intracameral injections of gentamicin and vancomycin were efficacious.^63,64 A 2002 retrospective study of direct intracameral cefuroxime injection in more than 32 000 cases in Sweden reported an endophthalmitis rate of 0.06%, which was significantly lower than comparable published rates.⁵¹ Twelve of the 13 culture-positive endophthalmitis organisms were cefuroxime resistant, including MRSA, suggesting that this method of administration was protective against organisms sensitive to the drug. Following this review, a 3-year prospective nonrandomized study of more than 225,000 cases in Sweden found a lower rate of endophthalmitis with intracameral cefuroxime than with topical antibiotic use alone.⁶⁵

The landmark multicenter prospective randomized study conducted by the ESCRS enrolled 16,603 patients and provides the strongest support for the efficacy of intracameral antibiotic prophylaxis.²⁰ The rates of culture-proven endophthalmitis were 0.050% and 0.025% in the two groups receiving intracameral cefuroxime prophylaxis compared with 0.226% and 0.176% in the two groups not receiving intracameral prophylaxis. Overall, direct intracameral cefuroxime injections resulted in a 5.86-fold decrease in the risk for culture-positive endophthalmitis.^20,66 No comparative studies suggest the optimal antibiotic agent for intracameral endophthalmitis prophylaxis.

The peer-reviewed literature generally supports the safety of using intracameral preparations of vancomycin, moxifloxacin, and several cephalosporins.^{52,64,67–71} However, both toxic anterior segment syndrome (TASS) and dosing errors are acknowledged risks of compounding medications for intraocular administration.⁷² One study concluded that intracameral cefuroxime was more cost-effective than topical fluoroquinolones.⁷³ Others have suggested that moxifloxacin has theoretical advantages for intracameral prophylaxis because of its potency and bactericidal activity and because the self-preserved commercial formulation avoids the need for compounding.⁵⁷ In the only study of its kind,⁷⁴ one group used serial aqueous taps following cataract surgery to show that a single intracameral injection of vancomycin 1.0 mg achieved an aqueous drug concentration that was four times the minimum inhibitory concentration for most gram-positive bacteria for longer than 24 hours. This study may represent what might be considered a depot effect, which might be why intracameral bolus of antibiotics is effective.

In 2012, single-use cefuroxime for intracameral use became commercially available in some countries in Europe. This product represents a step forward, as it significantly reduces the safety concerns associated with extemporaneous preparation. However, it does not completely eliminate the potential for dilutional errors and contamination, and there have been reports of anaphylaxis associated with its use. Interestingly, in a survey of ESCRS members published in 2014, only 74% of respondents were always or usually using an intracameral antibiotic in cataract surgery, despite the fact that it is recommended by the ESCRS and various European national ophthalmology societies.

Finally, no prospective clinical trial exists to support mixing antibiotics into the irrigating infusion bottle as a method of intracameral prophylaxis.

Toxic Anterior Segment Syndrome and Intracameral Antibiotic Agents

Toxic anterior segment syndrome is an acute sterile postoperative inflammation that can occur after uncomplicated or complicated cataract surgery and typically presents within 12 to 48 hours of surgery. Although problems with the cleaning and sterilization of instruments remains the most common risk factor associated with TASS, improper preparation of antibiotics for intracameral injection may also entail inaccuracies leading to TASS. Toxic anterior segment syndrome has been associated with the use of intracameral antibiotics in a small number of cases.⁷⁵

To reduce the risk for TASS, intracameral medications must be preservative free and have the proper concentration, pH, osmolarity, and osmolality. With specific regard to cefuroxime, the recommended dose of 1.0 mg in 0.1 mL has been shown to be well tolerated and to cause no ocular toxicity.⁵² Because of a misunderstanding in the dilution protocol, an outbreak of TASS was reported following the intracameral injection of cefuroxime mixed to deliver a dose almost 50 times higher than usual. The patients had significant postoperative inflammation of the anterior segment of the eye, with extensive macular edema.⁷⁶ Even following a strict dilution protocol under the controlled conditions of a research study, accurate dosage cannot be ensured.⁷²

The lack of a commercially available U.S. Food and Drug Administration (FDA)–approved antibiotic preparation for intracameral use means that intracameral antibiotics must be mixed by the surgeon, the operating room nursing staff, or a compounding pharmacy. A 2007 American Society of Cataract and Refractive Surgery (ASCRS) survey,⁷⁷ performed 8 months after the preliminary report of the ESCRS study, found that 77% of the more than 1,300 respondents were not using intracameral antibiotics. However, 82% stated that they would likely adopt this practice if a reasonably priced commercial preparation were available. Forty-five percent of the respondents not using intracameral antibiotic prophylaxis expressed concerns about the risk of injecting non-commercially prepared solutions. The survey determined that most respondents were using topical gatifloxacin or moxifloxacin (81%) and were initiating topical prophylaxis at least 1 day preoperatively (78%) and immediately postoperatively (66%). Because its control group did not mirror these practices, the ESCRS study was not able to determine whether intracameral cefuroxime was equal to, superior to, or of adjunctive benefit to the most commonly used topical antibiotic protocols preferred by the ASCRS survey population. The development, clinical investigation, and regulatory approval of a commercially available antibiotic for intracameral use would help eliminate potential toxicity and dilution problems.⁷⁸

Subconjunctival Injection

In the 2007 ASCRS survey,⁷⁷ only 13% of respondents were using subconjunctival antibiotic prophylaxis. Although there are no prospective randomized studies to support the use of subconjunctival antibiotic prophylaxis, some clinical evidence suggests a protective benefit. Retrospective studies from Canada,⁷⁹ the United Kingdom,⁸⁰ and Western Australia⁸¹ found statistically lower rates of endophthalmitis when subconjunctival antibiotics were given. The largest of these studies (Western Australia) was a population-based case-control study from 1980 to 2000.⁸¹

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