The Role of Preoperative Care in Reducing the Risk of Ocular Infection

Endophthalmitis is a rare but serious postoperative complication of cataract surgery and is possibly the most feared complication of any ocular surgery due to its potentially devastating consequences, including blindness. The rates of endophthalmitis in various ocular surgeries are well established (Table 1).^1–4 Endophthalmitis has been shown to occur in between 0.07% and 0.12% of cataract surgeries,^1,4 and with the transition from scleral tunnel incisions to clear cornea, no-suture surgeries, endophthalmitis in cataract patients is becoming more common.^5–9

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Risk Factors for Endophthalmitis

Preoperative Risk Factors

Risk factors for endophthalmitis include ophthalmic conditions, contact lenses, and systemic diseases:¹⁰

• ocular surface disease (ie, blepharitis, conjunctivitis, and dry eye syndrome)
• structural lid abnormalities
• lagophthalmic keratitis
• canaliculitis
• nasolacrimal duct obstruction
• contralateral ocular prosthesis
• diabetes mellitus
• immunosuppression

Intraoperative risk factors

Intraoperative risk factors for endophthalmitis include complicated or prolonged surgery.¹⁰ Surgical technique can also affect the rates of endophthalmitis. For example, inadequate isolation of lashes can increase the risk of infection, thus it is very important that when draping, the lashes and meibomian gland orifices are completely blocked by the drape. Povidone-iodine is well established as an excellent adjunct for reducing bacterial counts on the surface of the eye, and lack of its utilization during surgery can affect the rates of endophthalmitis. Prolonged surgery, vitreous loss, and wound leaks dramatically increase the risk of endophthalmitis. Externalized vitreous at the wound site and postoperative filtering blebs are also risk factors. The type and location of the incisions can affect the rates of endophthalmitis. The transition from a scleral tunnel incision that was covered by the conjunctiva to a limbal or clear corneal incision with sutures has led to increased rates of endophthalmitis if the limbal or corneal wound leaks. Careful construction of a symmetric, non-leaking wound is essential. The wound should be tested at the end of the case and if it is found to leak it should be closed with a suture.

Etiology of Endophthalmitis

Causative pathogens can be endogenous or exogenous. In the vast majority of cases, the infection is caused by the same pathogens located on the surface of the eye.^11,12 The potential for the patients’ own flora to cause endophthalmitis underscores the importance of wound construction, preoperative preparation, and draping in reducing this risk. Exogenous sources can be associated with surgery (eg, contaminated solutions, surgical instruments, intraocular lenses, operating room personnel, or an airborne pathogen).^13–16

Prevention of Endophthalmitis in Anterior Segment Surgery

A variety of measures can be taken prior to surgery to reduce endophthalmitis risk. Recent data indicate that examining the ocular surface for evidence of blepharitis and/or dry eye syndrome and addressing these conditions preoperatively not only reduces the risk of infection, but also improves surgical outcomes, such as quality of vision and faster visual recovery.¹⁷

During the preoperative examination, the surgeon should assess lid function by observing the blink rate and determining if there is a complete blink. Most importantly, the posterior lid margin should be examined for signs of meibomian gland disease, such as inspissation of glands, erythema and telangiectasias, pouting of oil, and gland drop-out. These findings increase the risk of postoperative complications.¹⁸ The conjunctiva should also be carefully examined. Conjunctival epithelium staining with lissamine green or Rose Bengal is effective in diagnosing dry eye syndrome.¹⁹ Tear volume and tear quality should also be assessed. Foamy tears are pathognomonic for meibomian gland disease, and there is potential for secondary dry eye syndrome from an unstable tear film. Schirmer testing is useful in the diagnosis of severe dry eye syndrome, especially in patients with Sjögren’s syndrome.²⁰

Prevalence of Dry Eye Syndrome

Dry eye syndrome is more common than originally believed.²¹ The worldwide prevalence is between 7% and 34%.²² The Beaver Dam population study found that 14.4% of adults aged 48 to 91 years had dry eye syndrome.²² Dry eye syndrome affects females more than males, as 16.7% of females in this study had dry eye syndrome, compared to 11.4% of males in the study.²² In both genders, the incidence increases with age. A study of 39,876 US women found that the age-adjusted prevalence of dry eye syndrome was 7.8% of females. The prevalence was 5.7% among women <50 years of age and 9.8% among women >75 years of age.²³ A cross-sectional prevalence survey among male participants aged 50 years and older in Physicians Health Studies I (N=18 595) and II (N=6848) indicated that the age-standardized prevalence of dry eye syndrome was 4.34% in these men.²⁴ The prevalence was 3.9% among men aged 50 to 54 years and 7.67% among men aged 80 years and older.²⁴

Treatment of Dry Eye Syndrome

There have been many advances in recent years in the understanding of the pathophysiology of ocular surface disease, which has led to more effective treatments. One of the most significant advances in the treatment of dry eye syndrome is recognition of the role of inflammation in its pathophysiology. Dry eye syndrome is now understood to be a chronic inflammatory disease of the accessory lacrimal glands, the conjunctiva, and the tear film. A treatment approach that reduces inflammation has changed the management of dry eye syndrome.

Cyclosporine

Studies have demonstrated that cyclosporine increases tear production, reduces cornea and conjunctival staining, and improves visual acuity.^25,26 Schirmer scores have been shown to improve from baseline for 59% of patients with chronic dry eye syndrome treated with cyclosporine.²⁵ Fifteen percent of patients improved by 10 mm, while only 5% of patients in the control group did so. Corneal staining of patients treated with 0.05% cyclosporine was also examined and compared to patients treated with vehicle. Significant improvements in corneal staining were observed at 4 months and at 6 months, but not at 1 month or at 3 months (Figure 1).²⁵ These results suggest that cyclosporine is effective, but there is a delay in onset of its effects. This is one of the disadvantages of cyclosporine treatment, as it can lead to difficulties with adherence. The physician must encourage the patient to continue the treatment regimen during the first 3 months even though they are not experiencing any beneficial effects of cyclosporine. Another limitation in the use of cyclosporine in the treatment of dry eye syndrome is that 17% of patients have discomfort and redness upon initiation of the drug, which can also affect treatment adherence.²⁷

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Corticosteroids

Corticosteroids are also effective in the treatment of dry eye syndrome, as they lead to decreased symptoms and decreased corneal staining compared to vehicle.²⁸ For example, patients treated with loteprednol experienced a statistically significant improvement from baseline in nasal bulbar conjunctival injection scores (hyperemia) after 2 weeks of treatment, while those receiving placebo did not.²⁸ The mean change after 4 weeks of treatment was -0.29 in the loteprednol group, a significant difference between these 2 groups (P=.0055). There was also a significant improvement in inferior tarsal conjunctival hyperemia scores in the loteprednol group (-0.19) compared to no change in the placebo group after 2 weeks of treatment (P=.0473).

Corticosteroids have been shown to improve symptoms of dry eye syndrome by controlling inflammation.²⁹ Inflammation is suppressed by decreasing the production of proinflammatory cytokines,²⁹ which have been detected in the conjunctiva and tear fluid of patients with dry eye syndrome. ^30–33 Proinflammatory cytokines stimulate the production of matrix metalloproteinase-9 (MMP-9) in corneal epithelial cells. Increased concentration and activity of MMP-9 has been detected in the tear fluid of patients with delayed tear clearance.³⁰ MMP-9 is believed to be involved in the pathogenesis of dry eye syndrome by dissolving the tight junction proteins that anchor the differentiated mucin-bearing apical corneal epithelial cells.³⁴ Corticosteroids have been demonstrated to decrease the production of matrix metalloproteinase enzymes, adding to their clinical benefit.³⁵

Loteprednol, an ester corticosteroid, is more lipophilic than ketone corticosteroids such as dexamethasone and prednisolone. This property leads to improved penetration as well as higher binding affinity to steroid receptors.^36,37 Loteprednol has been demonstrated to have a binding affinity that is 4.3 times that of dexamethasone.³⁷ These properties also result in an improved safety profile. The loteprednol molecule is only activated when it is bound to the receptor.³⁸ Unbound steroid is rapidly inactivated, which is postulated as the reason for loteprednol’s improved safety profile. This corticosteroid is associated with a significantly reduced incidence of IOP increase and a decreased risk of cataract. ^39–41 In a study comparing the incidence of clinically significant IOP elevations (≥10 mm Hg) associated with loteprednol and prednisolone acetate, the incidence of IOP elevations was 0.5% with vehicle, 1.7% with loteprednol, and 6.7% with prednisolone. ³⁹

Combination of cyclosporine and loteprednol

The effects of combining cyclosporine and loteprednol in the treatment of patients with dry eye syndrome were examined in a prospective trial.⁴² In the trial, 118 patients were divided into 2 groups. One group received loteprednol for 2 weeks, while the other group received artificial tears for 2 weeks. At the end of 2 weeks cyclosporine was added to the treatment regimens for both groups and continued until day 60. At day 60, both groups had improved corneal staining compared to baseline, but patients receiving loteprednol and cyclosporine had substantially less staining than the patients receiving artificial tears and cyclosporine (Table 2). Schirmer test scores were improved in both groups as well, but again were significantly more improved in patients receiving cyclosporine and loteprednol compared to cyclosporine and artificial tears. Both treatment regimens also reduced ocular surface disease index (OSDI) scores over 60 days, but OSDI scores were more significantly reduced with loteprednol and cyclosporine. Only 1% of patients in the loteprednol/cyclosporine group experienced discomfort with the initiation of therapy.

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When treating with topical anti-inflammatory agents, the Aesclepius Panel recommended that practitioners begin treatment with a potent, fast-acting corticosteroid to abrogate the inflammatory response and allay the propensity for stinging with cyclosporine, which can threaten compliance with the cyclosporine therapy. The consensus panel recommended loteprednol 4 times a day for 2 weeks, followed by twice daily loteprednol and twice daily cyclosporine for a total of 60 days (Figure 2).⁴³ At that time the effects of cyclosporine will manifest, and the loteprednol therapy can be tapered over the next several weeks. However, cyclosporine is a maintenance therapy, so if the patient experiences a breakthrough inflammatory reaction with redness and soreness, the loteprednol therapy should be restarted and continued for several days. Concomitant use of artificial tears is recommended throughout the treatment regimen. The panel acknowledged reports of statistically significant improvement in rapidity and side effect profiles for this approach.

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Treatment for severe dry eye syndrome

There are other treatment options when dry eye syndrome is severe.^26,44 Punctal plugs are effective in the management of severe dry eye syndrome. They should not be used until inflammation and lid diseases are controlled, to prevent the retention of inflammatory cytokines. If a patient has significant inflammatory findings on the surface of the eye, and punctal occlusion is immediately implemented, the patient’s symptoms may increase because inflammatory mediators are being trapped. This is especially true of evaporative dry eye disease observed in patients with meibomian gland disease.

Doxycycline is also effective in the management of severe dry eye syndrome. When using tetracycline antibiotics to treat severe dry eye syndrome, it is recommended to administer a lower dose than what would be used to treat an infection, as they are being used as an anti-inflammatory therapy in this situation. Fifty percent of patients administered oral doxycycline at 100 mg twice daily will experience gastrointestinal side effects. The same anti-inflammatory effects can be achieved with 50 mg once daily without the gastrointestinal side effects.

There is substantial evidence that autologous serum drops are effective in the management of the most severe cases of dry eye syndrome, such as Stevens-Johnson syndrome and Sjögren’s syndrome.

Nutritional supplements are effective in the management of meibomian gland disease as well as chronic dry eye syndrome. Eicosapentaenoic (EPA) and docosapentaenoic (DHA) poly-unsaturated fatty acids (fish oil) reduce inflammation,^45,46 and omega-3 polyunsaturated fatty acids (PUFA) thin meibomian gland secretions.^47,48

Guidelines for the Management of Dry Eye Syndrome

Several groups have established guidelines in the management of dry eye syndrome. For example, a panel of experts known as the Delphi Panel was convened by the Dry Eye International Task Force and charged to reach a consensus on diagnostic parameters for dry eye syndrome (Table 3).²⁶ Four levels of dry eye syndrome were established, accompanied by treatment recommendations based on these levels of severity: level 1 treatment focuses mainly on patient education and conservative management. At level 2, characterized by moderate to severe symptoms and minimal clinical signs, topical steroids and cyclosporine are recommended to effectively and rapidly control inflammation and to obtain a more favorable outcome. Artificial tears, gels, ointments, secretagogues, and nutritional supplements are also recommended at level 2.

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The American Academy of Ophthalmology (AAO) has established preferred practice patterns for the management of dry eye syndrome.⁴⁴ The AAO recommends that for mild dry eye syndrome, management should include patient education, environmental modifications, elimination of offending systemic or topical medications, aqueous enhancement (ie, artificial substitutes, gels/ointments), eyelid therapy, and treatment of contributing ocular factors. Management for moderate dry eye syndrome should include (in addition to treatments for mild dry eye syndrome) topical anti-inflammatory agents, systemic omega-3 fatty acid supplements, punctal plugs, and systemic side shields and moisture chambers. For severe dry syndrome, additional measures must be implemented, including systemic cholinergic agonists, systemic anti-inflammatory agents, mucolytic agents, autologous serum tears, contact lenses, correction of eyelid abnormalities, permanent punctal occlusion, and tarsorrhaphy.⁴⁴

Prevalence of Blepharitis

Blepharitis has been shown to be even more common than dry eye syndrome. In a telephone survey of 120 ophthalmologists, it was found that 37% of patients in their practices had a diagnosis of blepharitis.⁴⁹ A recent military study found that 5% of recruits had findings of blepharitis, while 71% of retirees had findings of blepharitis,⁵⁰ indicating that the risk of blepharitis increases with age.

In the telephone survey, blepharitis patients presented for evaluation for a variety of reasons.⁴⁹ Six percent of blepharitis patients were diagnosed during a routine physical examination. Interestingly, 16% of blepharitis patients were identified when they presented for a surgical evaluation. These are patients who are at increased risk for postoperative complications. Thirty-five percent of blepharitis patients presented for evaluation because they have symptoms of blepharitis. Forty-three percent presented with symptoms of dry eye syndrome,⁴⁹ such as evaporative tear loss due to an unstable tear film. This result highlights how dry eye syndrome and blepharitis are frequently present together in patients and physicians should look for symptoms of both when a patient presents with either condition. Dry eye syndrome is most commonly associated with a gritty foreign body sensation; blepharitis is usually associated with burning in response to free fatty acids and diglycerides. Furthermore, lid swelling is common with blepharitis.

Treatment of Blepharitis

Blepharitis can be treated with hyperthermia therapy, such as hot compresses and mechanical scrubs. Medicated lid scrubs are also helpful.²⁶ As previously stated, nutritional supplements are beneficial in the treatment of blepharitis. Oral doxycycline can also be used. Topical antibiotics such as bacitracin ointment and erythromycin ointment have been used to treat blepharitis. However, these ointments do not penetrate through the eyelids and therefore result in minimal effectiveness.

The newest medication for blepharitis is azithromycin, which is a macrolide with a broad spectrum of antibiotic activity and significant anti-inflammatory activity without the side effects of steroids. Importantly, azithromycin has the ability to penetrate ocular tissue, including conjunctiva and eyelid. This antibiotic has been used for years in the treatment of cystic fibrosis because of its excellent ability to penetrate tissue.⁵¹ Azithromycin has recently been found to be effective in the treatment of anterior and posterior blepharitis and has been documented to cause a change in the quality of meibomian gland secretions.⁵²

Decisions Regarding Ocular Surgery

For patients with significant findings of ocular surface disease at the time of surgical evaluation, it may be best to delay the surgery and treat the disease. Not only will the risk of endophthalmitis be reduced, but also the rate of postoperative visual recovery will be accelerated, leading to more satisfied patients.

There are also steps that can be taken intraoperatively to reduce the risk of surgical complications. Again, a careful preparation with povidone-iodine will reduce the risk of endophthalmitis. Careful isolation of the lid margins is critical as well. The epithelium must be protected. An anterior stromal puncture in an area of loose epithelium will stabilize that epithelium. Careful wound construction is also crucial. For example, suturing a leaky wound will reduce the risk of infection. Careful preoperative examination, aggressive treatment of any ocular surface disease, followed by meticulous surgical technique, will result in improved outcomes.

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