Topical Drugs in the Perioperative Period

Cataract removal with placement of an IOL is the most commonly performed surgical procedure in the United States, with an estimated 3 million cases per year. It is typically very safe and is associated with a low rate of complications.

The femtosecond laser has been a welcome addition to cataract surgery technology. The ability to fragment and soften the cataractous lens may reduce the need for ultrasound energy, and laser-assisted capsulorhexis automates this delicate and important step. As a result, the extent of intraocular manipulation can be reduced, along with the potential for agitating ocular tissues and inducing inflammation.

Another aspect that contributes to the safety of cataract surgery is the use of topical medications during the perioperative period to minimize inflammation and theoretically lower the risk for microbial infections. Not all topical drug formulations are created equal, however, and there can be important differences between branded and generic formulations of the antibiotics, corticosteroids, and nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used before and after cataract surgery.

ANTIBIOTICS

Topical antibiotics are often used before surgery and in the early postoperative period to reduce microbial populations on the eyelids, ocular surface, and ocular adnexa, theoretically limiting the potential for infections. The biggest concern is of the development of endophthalmitis, a vision-threatening complication that can destroy the eye in the most severe cases. Although the ability to prevent infection with prophylactic antibiotics has never been demonstrated in a prospective clinical trial, topical antibiotics are associated with few risks and complications, so the risk-benefit ratio for using them in the perioperative period has been considered favorable.

The role of intracameral antibiotics in cataract surgery remains controversial in the United States, although the practice is increasing worldwide. The prospective multicenter European Society of Cataract and Refractive Surgeons (ESCRS) study of antibiotic prophylaxis found a fivefold reduction in the risk of postoperative endophthalmitis with the use of intracameral cefuroxime compared with topical antiobiotics.¹ When practice patterns began to change in Europe as a result of these findings and the findings of other similar studies, the pharmaceutical industry there responded by introducing a formulation of cefuroxime for use in intracameral injection (Aprokam; Thea Pharmaceuticals).

No similar response has been forthcoming from US ophthalmic drugmakers, who would face significant hurdles to achieve FDA approval for a new intracameral agent. However, compounded combination medications formulated for intracameral use have become available in the US market (Dropless Cataract Surgery formulations from the compounding pharmacy Imprimis Pharmaceuticals). The formulations available from Imprimis contain a steroid and one or two antibiotics (triamcinolone acetonide and moxifloxacin [TriMoxi] and triamcinolone acetonide, moxifloxacin, and vancomycin [TriMoxiVanc]).

Both of these products contain moxifloxacin, a fluoroquinolone antibiotic that provides good coverage, with demonstrated activity against Gram-positive and Gram-negative microbes. However, the emergence of organisms resistant to moxifloxacin has been reported, and previous systemic use of a fluoroquinolone has been identified in vitro as a risk factor for fluorquinolone resistance in ocular cultures.² Therefore, the issue of potential resistance is important to consider in choosing a prophylactic agent. The American Society of Cataract and Refractive Surgery has recently issued a clinical alert regarding the association of hemmorhagic occlusive retinal vasculitis or HORV, a potentially blinding, late complication associated with intracameral vancomycin use.³ A registry has been formed to amass data, which may lead to a reduction in intracameral vancomycin use. In addition, in my experience, the steroid component of compounded formulations may not last sufficiently in eyes with darker irides, which have the potential for a more robust inflammatory response; there may be a risk in these patients for rebound iritis. For the time being, therefore, I have stuck with perioperative topical medications rather than moving to intracameral use.

The Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) surveillance study has found that resistance to one or more antibiotics is prevalent in ocular isolates.^4,5 In its most recent report, methicillin resistance was prevalent among staphylococcal isolates from ocular infections (42% to 49%), and many strains demonstrated multidrug resistance, including resistance to earlier-generation fluoroquinolones.⁵ These findings suggest that increased vigilance is warranted to reduce significant infection-related visual loss.

Besifloxacin (Besivance, Bausch + Lomb) is the latest topical ophthalmic fluoroquinolone antibiotic, specifically formulated for topical ophthalmic use, indicated for treatment of bacterial conjunctivitis.⁶ Because it has never been used systemically, common ophthalmic microorganisms have demonstrated little resistance to this relatively new agent.

I routinely start patients on a topical antibiotic 1 to 3 days before surgery, depending on the presence of comorbidities, such as diabetes or immunosuppression due to systemic disease or drugs. For patients who demonstrate poor lid hygiene, eyelid scrubs to reduce bacterial cell counts on the lashes and a full week of a broad-spectrum antibiotic ointment such as azithromycin is employed. I always check for silent dacryocystitis at the initial preoperative consultation by compressing the lacrimal sac, which can serve as a nidus for bacterial growth; this has saved my patients and me from significant difficulties in my more than 20 years of practice.

ANTI-INFLAMMATORY DRUGS: STEROIDS AND NSAIDs

Topical corticosteroids and NSAIDs function synergistically and complement one another, as they each suppress the formation of prostaglandin at different points on the arachadonic acid pathway. Studies have shown that patients using a steroid and an NSAID concurrently during the postoperative period exhibit less visually significant macular thickening and macular edema.^7-10 Unless a patient is a known steroid responder, I am of the opinion that both steroids and NSAIDs should be given postoperatively.

Intraoperatively, an NSAID can also be helpful in preventing intraoperative miosis and prostaglandin formation, which can be a significant cause of operative complications. Omidria (ketorolac and phenylephrine; Omeros) is a fixed-combination drug that can be placed in the irrigating solution to bathe the intraocular tissues throughout the surgical procedure, reducing pain and keeping the pupil dilated.

Corticosteroids

Three types of corticosteroids are available for ophthalmic use: ester steroids (eg, loteprednol etabonate ophthalmic suspension 0.5%; Lotemax, Bausch + Lomb), ketone steroids (eg, prednisolone acetate 1%; Pred Forte, Allergan), and halogenated steroids (eg, difluprednate ophthalmic emulsion 0.05%; Durezol, Alcon). Of the three, ester steroids are believed to carry the lowest risk of IOP elevation after cataract surgery because they are quickly broken down by esterases. Thus, an ester steroid is a good option for patients with known glaucoma or borderline IOP issues.

Glaucoma is not an absolute contraindication to the use of a topical steroid. In patients with risk factors for development of postoperative cystoid macular edema, such as macular drusen, epiretinal membrane, or a history of diabetes, the steroid is helpful to stave off the potentially serious complication. Antiglaucomatous medications may be used as needed if IOP elevation is seen postoperatively with the use of steroids. To reduce the risk of IOP elevation, I prescribe the steroid twice daily (steroids are usually indicated for use four times daily) and taper after a shorter than usual period.

In patients with dense cataracts, especially if I am not using a laser for nucleus fragmentation, difluprednate may be more useful. Anecdotally, I have found that steroids are more potent in suppressing and resolving inflammation and edema.

With regard to generic versus brand-name corticosteroids, there are important differences. Studies have found that branded medications are more consistent in both particle size and dose uniformity.^11,12 For example, with generic prednisolone, which is a suspension, the patient must shake the bottle before instillation to mix the ingredients; if this is not done, there may be inadequate steroid coverage from a watered-down drop and therefore an increased risk for inflammation.

NSAIDs

Watch it Now

Barry Schechter, MD, discusses generic medications.

I prescribe postoperative NSAIDs for all cataract patients unless there is a contraindication, such as a potential for developing corneal pathology, a previous diagnosis of rheumatoid arthritis, or a history of corneal melts. Topical NSAID use fell out of favor in the ophthalmic community due to well-publicized reports of corneal melts following use of some generic formulations. In the late 1990s, a survey by the American Society of Cataract and Refractive Surgeons identified at least 200 cases of corneal toxicity associated with the use of a generic formulation of diclofenac from Falcon Pharmaceuticals), and also cases associated with Voltaren (diclofenac sodium, Ciba Vision) and Acular (ketorolac tromethamine, Allergan).¹³ However, at least some of the involved eyes had unrecognized comorbid conditions that may have contributed to the development of the corneal issues.¹⁴

Because NSAID use can cause corneal issues in some patients, I use branded formulations whenever possible. Generally, these can be dosed less frequently and are more gentle to the ocular surface because they contain and therefore introduce less preservative. These formulations have been studied in rigorous clinical trials and are consistent from dose to dose. The generic formulations, despite having equivalent active ingredients and similar delivery systems, can differ in the inactive ingredients and in the amount contained in each drop, which can affect both the safety and efficacy of the medication.

CONCLUSIONS

I tailor the topical therapy regimen used in the perioperative period to the particular needs of the cataract surgery patient. When insurance coverage is not an issue, I prefer patients to use branded medications. I do not always have an objection to using generic medications per se, and they certainly may have a role for patients who are restricted by costs. Some patients’ insurance carriers insist on generics as the only option.

Anecdotally, patients tend to complain of burning and stinging upon instillation more often with generic than branded medications. In my bottom-line rationale regarding the branded-versus-generic debate, I ask myself, “What drop would I want to use if it were a family member’s eye undergoing surgery?” If the answer to that question is a branded medication, why should it be any different for patients who entrusts me with their vision? I expressed my preference for branded medications in a point/counterpoint in this publication 5 years ago,¹⁵ and I can report at this time that I have not changed my opinion since then.

1. Barry P, Seal DV, Gettinby G, et al. ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery: preliminary report of principal results from a European multicenter study. J Cataract Refract Surg. 2006;32:407-410.

2. Fintelmann RE, Hoskins EN, Lietman TM, et al. Topical fluoroquinolone use as a risk factor for in vitro fluoroquinolone resistance in ocular cultures. Arch Ophthalmol. 2011;129:399-402.

3. ASCRS. ASCRS and ASRS issue clinical alert on HORV association with intraocular vancomycin. http://www.ascrs.org/node/26102.

3. Haas W, Pillar CM, Torres M, et al. Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) 2009 surveillance study. Am J Ophthalmol. 2011;152(4):567-574.e3.

4. Asbell PA, Sanfilippo CM, Pillar CM, et al. Antibiotic resistance among ocular pathogens in the United States: five-year results from the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) Surveillance Study. JAMA Ophthalmol. 2015;133(12):1445-1454.

5. Besivance (besifloxacin ophthalmic suspension) 0.6%. Bausch + Lomb. 2016. http://www.bausch.com/ecp/our-products/rx-pharmaceuticals/rx-pharmaceuticals/besivance-ecp. Accessed July 18, 2016.

6. Wolf EJ, Braunstein A, Shih C, Braunstein RE. Incidence of visually significant pseudophakic macular edema after uneventful phacoemulsification in patients treated with nepafenac. J Cataract Refract Surg. 2007;33:1546-1549.

7. Lane SS, Modi SS, Lehmann RP, Holland EJ. Nepafenac ophthalmic suspension 0.1% for the prevention and treatment of ocular inflammation associated with cataract surgery. J Cataract Refract Surg. 2007;33:53-58.

8. Nardi M, Lobo C, Bereczki A, et al. Analgesic and anti-inflammatory effectiveness of nepafenac 0.1% for cataract surgery. Clin Ophthalmol. 2007;1(4):527-533.

9. Wittpenn JR, Silverstein S, Heier J, et al Acular for Cystoid Macular Edema (ACME) Study Group. A randomized, masked comparison of topical ketorolac 0.4% plus steroid vs steroid alone in low-risk cataract surgery patients.Am J Ophthalmol. 2008;146(4):554-560.

10. Roberts CW, Nelson PL. Comparative analysis of prednisolone acetate suspensions. J Ocul Pharmacol Ther. 2007;23(2):182-187.

11. Stringer W, Bryant R. Dose uniformity of topical corticosteroid preparations: difluprednate ophthalmic emulsion 0.05% versus branded and generic prednisolone acetate ophthalmic suspension 1%. Clin Ophthalmol. 2010;4:1119-1124.

12. NSAID Update. American Society of Cataract and Refractive Surgery, American Society of Ophthalmic Administrators. August 11, 1999.

13. Flach A. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc. 2001;99:205-210; discussion 210-212.

14. Schechter BA, Weston JM, Point/counterpoint: Are brand name agents required for cataract surgery? Advanced Ocular Care. March 2011.

Barry A. Schechter, MD
• director, Department of Cornea and External Diseases, Florida Eye Microsurgical Institute, Boynton Beach, Florida
• (561) 737-5500; baschechter@gmail.com
• financial disclosure: consultant to Abbott, Alcon, Bausch + Lomb, Omeros, Shire, and Sun.