When Regulations Stand in the Way of Good Medicine

Around the world, cataract surgery is one of the most frequently performed surgical procedures, with an astounding success rate. New developments occur regularly in surgical techniques and IOLs, continually improving patients’ visual outcomes. Postoperative endophthalmitis, while uncommon, remains the most serious potential complication of cataract surgery, but strategies for its prevention differ between the United States and Europe.

ENDOPHTHALMITIS PROPHYLAXIS

In 2004, the incidence of endophthalmitis in the United States was estimated to range from 0.06% to 0.20%.¹ Over time, surgical methods have evolved to prevent endophthalmitis, including the use a povidone-iodine scrub prior to cataract surgery, appropriate surgical draping, and the use of an antibiotic following surgery. Historically, physicians prescribed topical antibiotic drops one to four times daily for several weeks after surgery. However, increasing data are showing that intracameral antibiotics are more effective than topical antibiotics for preventing endophthalmitis.

In 2007, a landmark study by the European Society of Cataract and Refractive Surgeons (ESCRS) was published, showing a fivefold reduction in the risk of postoperative endophthalmitis, from 0.345% to 0.049%, when intracameral cefuroxime was used as prophylaxis instead of topical antibiotics.² This study and several others were impetus for the ESCRS to change its official guidelines on the prevention and treatment of endophthalmitis after cataract surgery to include the use of intracameral cefuroxime.³ The European ophthalmic industry, in response, developed Aprokam (cefuroxime 50 mg; Théa Pharmaceuticals). Aprokam received approval from the European Medicines Agency (EMA) in 2012.⁴ Its availability is likely a significant factor in European surgeons’ almost total adoption of intracameral rather than topical antibiotics as prophylaxis for endophthalmitis after cataract surgery.

In the United States, the course of practice patterns has not been the same. Following the European study, another study published in 2013 by a large US health system evaluated the change in postcataract endopthalmitis rates in relation to the adoption of intracameral injection of cefuroximine, moxifloxacin, or vancomycin at the end of surgery.⁵ A total of 16,264 cataract surgeries were performed during three time periods—2007 to 2008, 2009 to 2010, and 2011—during which the adoption of intracameral antibiotic injections steadily increased. Endopthalmitis rates for the respective periods were 0.313%, 0.143%, and 0.014%. Numerous studies have followed, and the efficacy of intracameral antiobiotics as endophthalmitis prophylaxis was recognized in the American Academy of Ophthalmology’s (AAO) Preferred Practice Pattern for adult cataract surgery in 2011.⁶

However, according to the American Society of Cataract and Refractive Surgery (ASCRS) annual survey, by 2014, only 20% to 30% of US surgeons were using intracameral injections of antibiotics.⁷ Despite high interest, most surgeons continue to rely on topical fourth-generation fluoroquinolones.

REGULATION AND REIMBURSEMENT

Although the data are convincing that intracameral antibiotics are better than topical antibiotics for endophthalmitis prophylaxis, there are barriers in the United States related to access and reimbursement. There is no US FDA-approved counterpart to Aprokam. Although the path to approval is clear for any company that wishes to apply for an approval, the two phase 3 clinical trials required by the FDA would cost roughly US$100 million. Despite that initial outlay, with 4 million cataract surgeries performed each year in the United States, a reasonable reimbursement of, say, US$100 per surgery would allow any company developing such a drug to obtain an adequate return on investment.

Unfortunately, there is currently no path toward even that modest level of reimbursement for this hypothetical product in the United States. The government agency that determines reimbursement for Medicare (US government–sponsored health insurance), which in turn influences the reimbursement practices of most private insurance companies, has ruled that any intraocular antibiotic injection would be bundled into the standard surgical fee for cataract surgery. Furthermore, the ruling also states that it would be illegal for patients to opt for the injection over topical antibiotics and pay for it themselves, as they do with premium IOLs. Thus, any surgeon who wants to use an intracameral injection of antibiotics has to cover the cost out of the surgical fees already paid.

OFF-LABEL DRUGS

With the lack of an FDA-approved pharmaceutical, some physicians have been opting to buy an antibiotic and draw it out on their own, but most continue to use topical drops. One compounding pharmacy, Imprimis Pharmaceuticals, has stepped in to fill the void. A government-regulated pharmacy, Imprimis has created patented combination drugs that combine preservative-free antibiotics with the antiinflammatory medications commonly prescribed after cataract surgery.

TriMoxi (triamcinolone 3 mg and moxifloxacin 0.2 mg) and TriMoxiVanc (triamcinolone 3 mg, moxifloxacin 0.2 mg, and vancomycin 2 mg) use a carrier adjuvant to bind the particles together to create a well-distributed micronized particle suspension that is stable at room temperature. Intracameral moxifloxacin has a broad spectrum of antibacterial activity against both gram-positive and gram-negative organisms and has a half-life of more than 1 hour.⁸ Several studies have found it to be as effective as intracameral cefuroxime in the prevention of endophthalmitis.⁹

Data presented at the 2014 ASCRS meeting included a retrospective chart review of 2,300 consecutive eyes that received a transzonular injection of TriMoxi after cataract surgery.¹⁰ Nineteen percent of patients had diabetes, and 5% had an epiretinal membrane; thus, 19% of the overall patient population received supplemental topical NSAIDs after surgery. There were no cases of endophthalmitis, and only 2.5% of patients (n=40) developed inflammation, which was defined as patients complaining of pain and/or photophobia accompanied by any cell and/or flare or by asymptomatic iritis with greater than 1+ cell/flare.

Of nearly 200,000 patient-specific doses of TriMoxi shipped to more than 500 doctors by the company, there have been only two known cases of endophthalmitis, both of which occurred several weeks after surgery in patients with dementia who reportedly engaged in frequent eye rubbing.

There are some differences with this approach, compared with the European standard of care. First, TriMoxi and TriMoxiVanc address inflammation and cystoid macular edema as well as endophthalmitis with a single injection, eliminating or greatly reducing the number of postsurgical drops necessary. Second, the injection is placed intravitreally versus intracamerally. This makes intuitive sense, as the posterior segment is where endophthalmitis would colonize and where cystoid macular edema occurs. Third, this remains an option with no reimbursement coverage, so surgeons using the so-called dropless technique must continue to cover the cost, a fact that hampers universal adoption. At US$20 per prescription, it is a manageable cost for something that I believe to be a great benefit to patients.

CONCLUSION

I feel it would be in the interest of patients, physicians, and the health care system as a whole to find a path to reimbursement for injectable prophylaxis at the time of surgery, as has been done in Europe. If not reimbursement, then allowing patients the option to pay for the injection out of pocket would help spur greater adoption of intravitreal antibiotics.

As an executive member of Cataract Surgeons for Improved Eyecare (improvedeyecare.org), a national membership association of ophthalmologists who are committed to the highest quality of care for our patients, I will continue to provide my patients with access to innovative, cost-effective, and practical ophthalmology solutions while lobbying our national health care system to do the same.

1. Du DT, Wagoner A, Barone SB, et al. Incidence of endophthalmitis after corneal transplant or cataract surgery in the Medicare population. Ophthalmology. 2014;121(1):290-298.

2. Endophthalmitis Study Group. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg. 2007;33(6):978-988.

3. Barry P, Cordoves L, Gardner S. ESCRS guidelines for prevention and treatment of endophthalmitis following cataract surgery: data, dilemmas and conclusions. 2013. www.escrs.org/endophthalmitis/guidelines/ENGLISH.pdf. Accessed June 27, 2016.

4. Théa Laboratories. Aprokam summary of product characteristics. http://www.medicines.org.uk/EMC/medicine/27397/SPC/Aprokam+cefuroxime+50mg+powder+for+solution+for+injection/. Accessed June 27, 2016.

5. Shorstein ND, Winthrop KL, Herinton LJ. Decreased postoperative endophthalmitis rate after institution of intracameral antibiotics in a Northern California eye department. J Cataract Refract Surg. 2013;39(1):8-14.

6. American Academy of Ophthalmology Cataract and Anterior Segment Panel. Preferred Practice Pattern: Cataract in the Adult Eye. American Academy of Ophthalmology. October 2011. http://www.aao.org/preferred-practice-pattern/cataract-in-adult-eye-ppp--october-2011. Accessed July 1, 2016.

7. Schwartz SG, Grzybowski A, Flynn HW Jr. Antibiotic prophylaxis: different practice patterns within and outside the United States. Clin Ophthalmol. 2016;10:251-256.

8. Matsuura K, Miyoshi T, Suto C, Akura J, Inoue Y. Efficacy and safety of prophylactic intracameral moxifloxacin injection in Japan. J Cataract Refract Surg. 2013;39(11):1702-1706.

9. Herrinton LJ, Shorstein NH, Paschal JF, et al. Comparative effectiveness of antibiotic prophylaxis in cataract surgery. Ophthalmology. 2016;123(2):287-294.

10. Galloway MS. Six-month report of patients receiving TriMoxi. Paper presented at: the ASCRS Annual Meeting; April 2015; San Diego.

Richard L. Lindstrom, MD
• Private practice, Founder, Minnesota Eye Consultants, Bloomington
• Adjunct Professor Emeritus, University of Minnesota Department of Ophthalmology
• rllindstrom@mneye.com
• Financial disclosure: Consultant (Imprimis Pharmaceuticals)