s CATARACT SURGERY INTRACAMERAL ENDOPHTHALMITIS PROPHYLAXIS: WHERE WE STAND Surgeons discuss the practical implications of a recent meta-analysis.

BY LISA BROTHERS ARBISSER, MD; FRANCIS S. MAH, MD; DAVID F. CHANG, MD; RICHARD KENT STIVERSON, MD; AND STEVE A. ARSHINOFF, MD, FRCSC

Routine endophthalmitis prophy- studies supporting this assertion.2 Significant risks It is worth remembering that topical antibiotic laxis with an intracameral (IC) have come to light for other antibiotic choices but prophylaxis is also an off-label practice and hardly antibiotic for cataract surgery not for self-preserved Vigamox (moxifloxacin HCl oph- without economic and biome-altering consequences. is vastly underused in the thalmic solution 0.5%, Alcon), despite the manufac- For surgeons who wish to use IC prophylaxis and United States compared with turer’s legal labeling added to the bottle that reads, do not choose a compounding route, Dr. Arshinoff internationally. Since the ESCRS study, in 2007,1 and its “not for intraocular use.” has provided a detailed how-to guide; it is a discontinuation on ethical grounds, owing to the star- In addition to the enlightening meta-analysis template that I believe has benefited my patients tling decrease in endophthalmitis in the treatment arm, by Bowen and colleagues that is the focus of this (see Dr. Arshinoff’s Method of Preparation). many countries have made IC antibiotics available, and article,3 I would like to draw readers’ attention to ASCRS has announced its intention to perform some have even made them mandatory. At the end of an editorial published in Ophthalmology in 2016 that a multicenter randomized prospective trial that that landmark year, I began following the lead of Steve detailed a possible way to surmount the main barrier will require more than 75,000 patients to reach A. Arshinoff, MD, FRCSC, regarding the off-label use of to IC prophylaxis in the United States: the lack of significance. This will hopefully provide a definitive moxifloxacin, and I never again saw endophthalmitis an FDA-approved preparation.4 Given that 3 million answer and lead to uniform adoption of intracameral after cataract surgery in thousands of patients. The cataract surgeries are performed yearly in this coun- antibiotic prophylaxis. I hope most surgeons will not suggested moxifloxacin dosage has been adjusted try, an estimated 2,000 eyes could be saved by IC wait for the results far into the future. upward to a minimum inhibitory concentration to over- antibiotic prophylactic use. Big data from the Aravind CRST and I invited several well-known experts in our come laboratory-measured resistance of organisms Eye Hospital System5 and elsewhere are confirmatory field to interpret the insights provided by the recent most likely implicated in endophthalmitis. for me and may be enough to convince others. Kaiser meta-analysis and to comment on their own practices. First, do no harm. There is ample evidence of the Permanente acted on its own big data6 prior to the safety of IC moxifloxacin; I conducted one of many evidence from India. —Lisa Brothers Arbisser, MD

The main take-away messages of the topical medications did not appear to be meta-analysis by Bowen and colleagues of benefit in the meta-analysis. are as follows.3 In terms of the volume My preferred IC agent is moxifloxacin. of studies and the volume of patients, IC I am not using IC vancomycin for two cefuroxime has the greatest amount of reasons. First, HORV is a devastating FRANCIS S. MAH, MD support in the literature and vancomycin complication, potentially worse than the lowest. Of the three agents, cefurox- the endophthalmitis the antibiotic was Nobody is going to perform a ime was the least effective, although it meant to prevent. Second, the AAO clinical trial comparing IC cefuroxime, was more efficacious than topical drops. and the Centers for Disease Control moxifloxacin, and vancomycin to see if Moxifloxacin was more effective than issued guidance against using this medi- one of these agents is superior to the cefuroxime and was associated with cation as a prophylactic agent. others. A meta-analysis of the litera- less toxicity. Most effective of the three ture is the next best thing; it helps to agents was vancomycin, but it has been ESTABLISHING TRUE ALLERGY decrease the biases present in individu- associated with hemorrhagic occlusive IC anaphylaxis has been associated al articles to uncover general findings. retinal vasculitis (HORV). Interestingly, with cephalosporins such as cefuroxime

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and cefazolin. At most, approximately 10% of patients who are allergic to DR. ARSHINOFF’S METHOD OF PREPARATION penicillin are also allergic to cephalo- sporins. A history of penicillin allergy SUPPLIED withdrawn into the same syringe. The two would therefore raise my concern over Moxifloxacin HCl ophthalmic solution 0.5% substances will be mixed by the turbulence of the use of IC cefuroxime. Compared (Vigamox, Alcon) = 500 µg/0.1 mL aspiration and rolling the syringe. The circulat- with beta-lactam antibiotics such as the ing nurse injects 0.8 mL of the Vigamox solution cephalosporins, an advantage of fluo- GOAL into a medicine cup on the surgical tray. roquinolones is that they are generally 150 µg/0.1 mL (dilution: 3 parts Vigamox + 3. The scrub nurse draws up 0.6 mL of the Vigamox associated with fewer allergies. 7 parts BSS [Alcon]) The first step to establishing true solution into a tuberculin syringe to hand to the In other words, to achieve 150 µg/0.1 mL, allergy is the history. To my mind, surgeon. patients who state that some pills simply dilute the eye drops to 30% concentration 4. The surgeon expels 0.1 mL to be sure there upset their stomach in the past do of supplied Vigamox are no bubbles and then injects 0.3 to 0.4 mL not have a true allergy. If they say they via the sideport incision, as the last step of developed hives or a rash, then I am METHOD cataract surgery, under the distal edge of the more cautious. Because I work in a Inject 0.3 to 0.4 mL Vigamox 150 µg/0.1 mL capsulorrhexis. Then, as the eye is exited, a clinic, urgent care is nearby. In these at the end of the case = 450 to 600 µg → 1.0 to final spurt of injection is used at the incision cases, I will therefore instill a single 1.2 mg/mL in the anterior chamber (AC). to hydrate the incision and ensure the AC is left drop of a fluoroquinolone in the Essentially, this is an exchange of most of the pressurized (Figures 1 and 2). This is a planned patient’s eye and observe him or her newly pseudophakic AC volume (0.5 mL) with the exchange of most of the AC contents and is for a reaction in the clinic. If nothing Vigamox solution. The volume indicated is what is therefore easy to do. happens, I will plan to use IC moxiflox- likely left in the AC at the end of surgery. acin on the day of surgery. Obviously, a PERSONAL EXPERIENCE history of anaphylaxis is a clear contra- DETAILED INSTRUCTIONS Dr. Arshinoff has used variations of this method indication to a medication. 1. From a new bottle of Vigamox, 3 mL is withdrawn in more than 8,700 cases and observed no toxicity If a patient has an allergy to fluo- into a 12-mL syringe with a sterile needle. to date. roquinolones but not to beta-lactam 2. From a new 15-mL bottle of BSS, 7 mL is antibiotics, I will use cefazolin 2.5 mg in 0.1 mL instead of moxifloxacin.

ACCESSING IC ANTIBIOTICS More US cataract surgeons would use IC antibiotics if an FDA-approved drug were available. Because that is not the case, one option is to obtain an IC formulation from a compounding pharmacy such as Leiters, a hospital pharmacy, or a company such as Imprimis Pharmaceuticals or Ocular Science. Figure 1. Via the sideport incision, Dr. Arshinoff Figure 2. During the injection, the cannula (1, green) A second option is either to dilute administers an intracameral injection of moxifloxacin. depresses the IOL slightly so that the moxifloxacin commercially available moxifloxacin He favors a hockey stick cannula because he can perform solution bathes the IOL within the capsular bag. As a or to use it straight out of the bottle. the injection slowly, thus deepening the capsular bag sequestered space, the capsular bag is an excellent The literature describes using any- and allowing him to rotate the IOL slightly to the desired location for bacterial growth. The surgeon performs thing from 50 to 500 mg in 0.1 mL at alignment. He continues the injection as the instrument final hydration of the incision (2, purple) while the end of surgery. As far as I know, exits the eye, ensuring an exchange of most of the removing the cannula from the eye. there have been no published reports aqueous with the moxifloxacin solution and pressurization of the AC. If concerned that the sideport incision will about using dilute generic moxifloxa- leak, Dr. Arshinoff will hydrate it prior to injecting the cin, and Moxeza (moxifloxacin HCl moxifloxacin, but usually he simply hydrates the incision ophthalmic solution 0.5%, Alcon) as the cannula exits the eye. should definitely not be injected intracamerally.

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defend the off-label use of IC vanco- Although a higher threshold for sta- mycin when alternative antibiotics tistical significance might increase the were available. chance of a false negative, multiple Based on our Aravind studies, I studies—even with smaller sample have switched to IC moxifloxacin sizes—would reduce the chance of DAVID F. CHANG, MD supplied by a 503B compounding false positives. I highly recommend pharmacy. Imprimis Pharmaceuticals that readers watch the video, “Is Most The recent meta-analysis by Bowen and Leiters are the largest 503B Published Research Wrong?” by Derek and colleagues pools data from outsourcing facilities that can supply Muller, BSc, PhD (bit.ly/2bbI6oF). Even 17 studies published over the past moxifloxacin for IC injection. randomized, prospective studies should 2 decades. Apart from the ESCRS ran- be regarded with skepticism when the domized clinical trial,1 these were all sample size is small and significance is observational studies. When pooled, based on a probability of less than 0.05. however, more than 925,000 eyes can I do not believe the work by Bowen be analyzed, providing a large amount and colleagues will change US cataract of data supporting the safety and effi- surgeons’ IC choices. Cefuroxime will cacy of routine IC antibiotic prophy- not be widely adopted in the United laxis for phacoemulsification. RICHARD KENT STIVERSON, MD States because of the risk of anaphylax- One of the more interesting aspects is and bacterial resistance profiles that is the comparison of different IC The meta-analysis by Bowen and are significantly different from those in antibiotic agents. The meta-analysis colleagues confirms the efficacy of IC Europe (in part because of antibiotic includes a large observational study of antibiotics in preventing postcataract abuse in the United States). Kaiser IC moxifloxacin from the Aravind Eye surgery endophthalmitis,3 as shown started with cefuroxime because that Hospital System that my colleagues in the very large ESCRS,1 Kaiser,6 and was the antibiotic of the preexisting and I published in 2017, which signifi- Aravind studies.5 Although I am not studies, but many Kaiser doctors have cantly expands the pooled data for this qualified to comment on the statistical switched to moxifloxacin. The specter drug.5 The comparative endophthal- rigor of this meta-analysis, rigor is cru- of HORV is such that most ophthal- mitis rates were 0.033% for cefuroxime, cial and seems to be well documented mologists have abandoned or will 0.015% for moxifloxacin, and 0.011% in this study. The number of meta- abandon IC vancomycin. Moxifloxacin for vancomycin. This suggests that analyses in medicine has increased will be the most commonly used IC both moxifloxacin and vancomycin markedly from 334 worldwide in 1991 antibiotic in the United States. provide better coverage than cefurox- to 5,000 in 2012 and 10,000 in 2017. I stopped using topical antibiotics ime. The data also indicate that add- It is important to note that meta- a year ago. Although I understand the ing topical antibiotic prophylaxis may analyses are only as good as the trials belt-and-suspenders approach of using provide no benefit over IC antibiotic included; in other words, including both topical and IC antibiotics that prophylaxis alone. large numbers of low-quality studies many surgeons advocate, there is simply A joint task force formed by the does not make a meta-analysis more no evidence to support it. Moreover, ASCRS and the American Society of valid. Bowen and colleagues excluded a large number of cataract surgery Retina Specialists, which I cochaired, several IC studies from their meta- patients receive anti-VEGF injections or concluded that HORV was a analysis, which gives me more confi- will in the future. The retina literature type III hypersensitivity to vancomy- dence in their findings. suggests that repeated prophylactic cin.7 Although we suggested that the Prospective randomized clinical trials topical antibiotics might be contrain- use of IC vancomycin should be left remain the gold standard for evidence- dicated.8 A week of topical antibiotic to the individual surgeon’s discretion, based medicine, but their prohibitive prophylaxis after cataract surgery would the AAO Cataract Preferred Practice cost is such that high-quality, reliable certainly fall under this concern. Patterns and the FDA have since dis- meta-analyses will assume increasing I use the same formulation as couraged using IC vancomycin because importance in answering doctors’ big Dr. Arshinoff (see Dr. Arshinoff’s of the risk of HORV. I personally used questions. Meta-analysis gave rise to Method of Preparation). Like him, I per- IC vancomycin routinely for 18 years big data. form immediately sequential bilateral without any known complications. In my opinion, changing statistical surgery. The importance of IC antibi- Should a case of HORV ever occur, significance to P < .005 would make otic prophylaxis cannot be overstated. however, these strong pronounce- a lot of published research more His formulation allows more volume ments would make it difficult to valid and worthier of consideration. at a desired concentration so that

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most of the aqueous can be replaced with moxifloxacin solution. There is AT A GLANCE usually enough left over that I can also perform some stromal hydration of s A meta-analysis compared the safety and efficacy of intracameral the incisions. That said, the success of cefuroxime, moxifloxacin, and vancomycin in preventing endophthalmitis staggering numbers of patients in the Aravind study,5 with such small vol- after phacoemulsification cataract surgery. umes of moxifloxacin, suggests that my concerns are unfounded. s The meta-analysis pooled data from 17 studies published over the past 2 decades and included more than 925,000 eyes. This large amount of data supported the safety and efficacy of routine IC antibiotic prophylaxis.

carefully, it is because subtherapeutic dilution error have ever been reported. doses of the drug were used.10,11 The Another drawback to cefuroxime is STEVE A. ARSHINOFF, MD, FRCSC sequential analysis approach thus that, as a relative of penicillin, it car- gradually clarifies the answers to the ries a much higher risk of allergy than One of the great strengths of the questions all of us really want to ask the other two drugs. Vancomycin has research by Bowen and colleagues is and is more useful but much more recently been associated with a small that it included observational stud- time-consuming for the reader than risk of the devastating allergic com- ies as well as the sole randomized meta-analyses. I will address some of plication of HORV. With vancomycin, controlled study in this field,1 yielding these questions here. it thus appears that we are trading a much broader depth of informa- one rare devastating risk for another. tion than is available from the recent DO IC ANTIBIOTICS WORK? Moxifloxacin is therefore the safest of Cochrane review on the same subject.9 Adding up studies on the IC admin- the three drugs. Bowen and colleagues concluded istration of cefuroxime, moxifloxacin, Also worth noting is that data from that, whether or not postoperative and vancomycin for cataract surgery the Swedish national database recently topical antibiotics were used, IC endophthalmitis prophylaxis yields revealed that failures with IC cefurox- antibiotics all achieved statistically an aggregate of more than 6 million ime are often Enterobacter cases, which significant decreases in rates of infec- surgeries in the database. Every study are difficult to treat and usually result tion, with no agent being statistically (except two in which too low a drug in devastating blindness.13 In contrast, significantly better than the other dose was used10,11) demonstrated failures with moxifloxacin are generally two. (Statistical analysis also failed to a reduction in postoperative endo- easy-to-treat cases of Staphylococcus, demonstrate any additional benefit of phthalmitis cases of about 80% when and these patients generally retain postoperative topical antibiotics.) IC prophylaxis was used. The efficacy of good vision. Furthermore, Libre and The study by Bowen and colleagues IC antibiotics is no longer in question. Mathews recently demonstrated that is excellent, but the problem with only moxifloxacin is effective against all meta-analyses is that they must, by WHICH IC ANTIBIOTIC IS BEST? 18 strains of endophthalmitis isolates their methodology, group data from In terms of efficacy, cefuroxime, from the Bascom Palmer Eye Institute.14 different studies conducted at differ- moxifloxacin, and vancomycin ent times and analyze this aggregate all produce similar reductions in SHOULD IC ANTIBIOTICS BE USED FOR data. Although this method produces the incidence of postoperative IMMEDIATELY SEQUENTIAL BILATERAL useful results, the best understanding endophthalmitis. As the database CATARACT SURGERY? and conclusions come from studying grows, I expect moxifloxacin to turn Absolutely. In 2009, the International the articles successively and reread- out to be the best—but only when Society of Bilateral Cataract Surgeons ing previous ones to discover what the sample size becomes huge because issued a recommendation that IC errors might have been made in each the difference in efficacy is small. antibiotics be used for immediately study and corrected by a later author The use of cefuroxime is of concern sequential bilateral cataract surgery. or group. For example, two studies because dilution errors have been The society’s study of endophthalmitis from Japan failed to demonstrate a shown to cause severe ocular dam- after bilateral cataract surgery found statistically significant benefit of IC age.12 Moxifloxacin is much easier to that, in more than 125,000 eyes, the moxifloxacin, but when they are read dilute, and no complications from a infection rate when IC antibiotics were

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cataract surgery: does the preponderance of the evidence mandate a global n [email protected] used was 1:16,890, the lowest infection change in practice? Ophthalmology. 2016;123(2):226-231. 15 5. Haripriya A, Chang DF, Ravindran RD. Endophthalmitis reduction with n Financial disclosure: None rate reported in any study to date. intracameral moxifloxacin prophylaxis: analysis of 600,000 surgeries. Ophthal- I have used IC moxifloxacin for almost mology. 2017;124(6):768-775. 6. Shorstein NH, Winthrop KL, Herrinton LJ. Decreased postoperative STEVE A. ARSHINOFF, MD, FRCSC 9,000 consecutive eyes with no nega- endophthalmitis rate after institution of intracameral antibiotics in a Northern tive ocular side effects of the drug. I was California eye department. J Cataract Refract Surg. 2013;39(1):8-14. n Directing Partner, York Finch Eye Associates, Toronto 7. Witkin AJ, Chang DF, Jumper JM, et al. Vancomycin-associated hemorrhagic n the first in the world to use IC moxi- occlusive retinal vasculitis: clinical characteristics of 36 eyes. Ophthalmology. Associate Professor, Department of Ophthalmology 2017;124(5):583-595. and Vision Sciences, University of Toronto floxacin and to propose its use generally. 8. Bande MF, Mansilla R, Pata MP, et al. Intravitreal injections of anti-VEGF agents and antibiotic prophylaxis for endophthalmitis: a systematic review and n [email protected] Early on, when I was using a low dose meta-analysis. Sci Rep. 2017;7(1):18088. 9. Gower EW, Lindsley K, Tulenko SE, et al. Perioperative antibiotics for preven- n Financial disclosure: Paid consultant (Alcon) (100 µg in 0.1 mL), one patient devel- tion of acute endophthalmitis after cataract surgery. Cochrane Database Syst oped a resistant strain of Staphylococcus Rev. 2017;2:CD006364. 10. Matsuura K, Suto C, Akura J, Inoue Y. Bag and chamber flushing: a new DAVID F. CHANG, MD epidermidis endophthalmitis, but with method of using intracameral moxifloxacin to irrigate the anterior chamber n routine endophthalmitis treatment, and the area behind the intraocular lens. Graefes Arch Clin Exp Ophthalmol. Clinical Professor, University of California, San 2013;251(1):81-87. Francisco visual acuity promptly improved to 11. Matsuura K, Miyoshi T, Suto C, et al. Efficacy and safety of prophylactic intracameral moxifloxacin injection in Japan. J Cataract Refract Surg. n Private practice, Los Altos, California 20/25. I have since increased the dose I 2013;39(11):1702-1706. n use and recommend to cover even the 12. Olavi P. Ocular toxicity in cataract surgery because of inaccurate preparation CRST Editor Emeritus and erroneous use of 50mg/ml intracameral cefuroxime. Acta Ophthalmol. n most resistant strains (see Dr. Arshinoff’s 2012;90(2):e153-154. [email protected] 13. Monta P. Antibiotics revisited. Paper presented at: XXXV Congress of the n Financial disclosure: None Method of Preparation). About 80% of ESCRS; October 8, 2017; Lisbon, Portugal. my last 14,000 cataract surgeries have 14. Libre PE, Mathews S. Endophthalmitis prophylaxis by intracameral anti- biotics: in vitro model comparing vancomycin, cefuroxime, and moxifloxacin. FRANCIS S. MAH, MD been immediately sequential bilateral J Cataract Refract Surg. 2017;43(6):833-838. 15. Arshinoff SA, Bastianelli PA. Incidence of postoperative endophthalmitis n Scripps Health, La Jolla and San Diego, California cataract surgery. n after immediate sequential bilateral cataract surgery. J Cataract Refract Surg. 2011;37(12):2105-2114. n [email protected] 1. Endophthalmitis Study Group, European Society of Cataract & Refractive n Financial disclosure: Consultant (Alcon); Medical Surgeons. Prophylaxis of postoperative endophthalmitis following cataract advisory board (Ocular Science) surgery: results of the ESCRS multicenter study and identification of risk factors. LISA BROTHERS ARBISSER, MD J Cataract Refract Surg. 2007;33(6):978-988. 2. Arbisser LB. Safety of intracameral moxifloxacin for prophylaxis n Emeritus position, Eye Surgeons Associates, the RICHARD KENT STIVERSON, MD of endophthalmitis after cataract surgery. J Cataract Refract Surg. Iowa and Illinois Quad Cities 2008;34(7):1114-1120. n Colorado Permanente Medical Group, Lone Tree, 3. Bowen RC, Zhou AX, Bondalapati S, et al. Comparative analysis of the safety n Adjunct Professor, John A. Moran Eye Center, and efficacy of intracameral cefuroxime, moxifloxacin and vancomycin at the Colorado end of cataract surgery: a meta-analysis [published online ahead of print Janu- University of Utah, Salt Lake City ary 11, 2018]. Br J Ophthalmol. doi:10.1136/bjophthalmol-2017-311051. n [email protected] 4. Javitt JC. Intracameral antibiotics reduce the risk of endophthalmitis after n Member, CRST Advisory Board n Financial disclosure: None

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