The Dose & Administration of Intracameral Moxifloxacin (note: all intracameral antibiotic use is off-label) Poster P10 Submission # 981672 Full Address: Dr. Steven Arshinoff 316-2155 Finch Ave. W. Toronto, Ontario, Canada ifix2is@sympatico.ca Dr. Brent Zanke MaRS Center 200-101 College St. Steve A. Arshinoff MD FRCSC Humber River Regional Hospital Departments of Ophthalmology and Vision Sciences, University of Toronto & McMaster University Financial Disclosures : Alcon Laboratories Inc. - Consultant

The Dose & Administration of Intracameral Moxifloxacin Purpose: To assess the desirability of moxifloxacin as an intracameral antibiotic for endophthalmitis prophylaxis. To determine the optimal dose of intracameral moxifloxacin based upon best available current evidence Methods: Review of ophthalmologic and microbiologic literature and current practices, as well as experience to date.

Intracameral antibiotic prophylaxis: Drugs that have been used & reported. Class Drug Dose / 0.1 cc Complex Glycopeptide - Vancomycin 1 mg Cephalosporins: - Cefazolin (G1) 1- 2.5 mg - Cefuroxime (G2) 1 mg G4 fluoroquinolones - Gatifloxacin 100 µg - Moxifloxacin 100-500 µg

Recent Intracameral Cephalosporin Data As Baseline Reference for Infection Rates Due to promotion of the ESCRS study protocol and results6, the best baseline data to estimate current infection rates with and without intracameral antibiotics, comes from numerous recent studies of intracameral cephalosporins. The table on the following slide illustrates a weight-averaged sum (weighted by numbers of cases) and risks of endophthalmitis reported in these studies1-7. 1Garat M, Moser CL, Martin-Baranera M, Alonso-Tarres C, Alvarez-Rubio L. Prophylactic intracameral cefazolin after cataract surgery: Endophthalmitis risk reduction and safety results in a 6-year study. JCRS 2009; 35: 637-42. 2Romero P, Mendez I, Salvat M, et al. Intracameral cefazolin as prophylaxis against endophthalmitis in cataract surgery. J Cataract Refract Surg 2006: 32: 438-441 (March). 3Montan PG, Wejde G, Koranyi G, Rylander M. Prophylactic Intracameral Cefuroxime. JCRS 2002; 28: 977-981, 982-7. 4Wejde G, Montan P, Lundstrom M, Stenevi U, Thorburn W. Endophthalmitis following cataract surgery in Sweden: national prospective survey 1999-2001. Acta Ophthalmol Scand 2005; 83:7-10. 5Lundstrom M, Wejde G, Stenevi U et al. Endophthalmitis after cataract surgery: A nationwide prospective study evaluating incidence in relation to incision type and location. Ophthalmology 2007; 114:886-870 6ESCRS Endophth. Study group. Prophylaxis of postoperative endophthalmitis following cataract surgery: Results of the ESCRS multicenter study and identification of risk factors. JCRS 2007; 33:978-988. 7García-Sáenz MC, Arias-Puente A, Rodríguez-Caravaca G, Bañuelos JB. Effectiveness of intracameral cefuroxime in preventing endophthalmitis after cataract surgery: Ten year comparative study. JCRS 2010; 36 203-7.

Published intracameral cephalosporin studies all show 80-90+% endophthalmitis rate reduction with use of intracameral cephalosporins. Study IC Antibiotic years n POE No IC POE IC rate p 1Garat, Barcelona Cefazolin 2.5 mg/0.1ml 2004 -2007 18,603 1/240 1/2,130 0.047% <0.001 2Romero Reus, Spain Cefazolin 1mg/0.1 ml 2001 -2004 7,268 1/160 1/1,809 0.055% 3Montan, Sweden Cefuroxime 1mg/0.1 ml 1990 -2000 66,200 1/383 1/1,600 0.06% 4Wejde, Sweden, NCR Cefuroxime 1mg/0.1ml. 1999-2001 188,151 1/454 1/1,887 0.053% 5Lundström, Sweden NCR 2002 – 2004 225,471 1/290 1/2,231 0.045% 6Barry, ESCRS Study Cefuroxime 1mg/0.1ml 2003 - 2006 16,603 1/337 1/1,621 0.07% 7Garcia –Saenz Madrid, Spain Cefuroxime 1.0 mg/0.1 ml 1999 -2008 13,652 1/169 1/2,352 0.043% Sum Weight averaged 90 - 08 535,948 1/331 1/1,977 0.05% NCR = Swedish national cataract registry, POE = Post –Operative Endophthalmitis, IC = intracameral antibiotic

Are other intracameral antibiotics better than cefuroxime? The ESCRS study did not compare efficacy of different IC antibiotics. It tested only IC cefuroxime. We have collected data, over the past 2 years from bilateral cataract surgeons, members of the iSBCS (international Society of Bilateral Cataract Surgeons), on their unilateral and bilateral procedures with all antibiotic regimens, a summary of which appears on the next slide. Although huge numbers are needed to prove superiority of one antibiotic over another, because of the extremely low incidence of post-operative endophthalmitis in all groups, both vancomycin and moxifloxacin tended to have lower infection rates than cefuroxime.

Endophthalmitis in Bilateral Cataract Surgery 2010 study* IC Antibiotic N (eyes) Endophalmitis (POE) cases POE rate *p Immediately Sequential Bilateral Cataract Surgeries only vs. no IC No IC antibiotic 23,847 12 1:1,987 0.05% reference Cefuroxime (cef) 45,873 5 1:9,175 0.01% <0.01 Vancomycin 15,240 Moxifloxacin 10,094 0.001 Immediately & Delayed Sequential Bilateral Cataract Surgeries vs. cef. 19,722 0.17 35,194 1 1:35,194 0.003% 0.22 Moxifloxacin & Vancomycin 552 All IC antibiotic cases (vs. no IC) 101,341 6 1:16,890 0.006% <0.0001 *p = www.openepi.com 2 tailed Mid p exact *The incidence of postoperative endophthalmitis after immediately sequential bilateral cataract surgery. 2011 in press

Intracameral moxifloxacin *Usual MIC of Staphylococci to moxifloxacin = 0.06 mg./L We had used intracameral injections of 100 µg in 0.1 cc. in over 3,500 cases without any infections. In January 2010, one patient developed unilateral post-operative endophthalmitis with a resistant strain of Staphylococcus epidermidis, MIC 8mg/L., 133x higher than usual MIC! **MIC90 for Staphylococci to moxifloxacin has been reported as high as 32 mg/L. ***Montan et al: Aqueous concentrations of antibiotics drop by 50% every ½ hour. The following slide shows the calculation of IC moxifloxacin doses & effect. *Balzli CL, Caballero AR, Tang A, Weeks AC, O’Callaghan RJ. Penetration and effectiveness of prophylactic fluoroquinolones in experimental methicillin-sensitive or methicillin-resistant Staphylococcus aureus anterior chamber infection. J Cataract Refract Surg 2010; 36:2160–2167. ** Miller D, Flynn PM, Scott IU, Alfonso EC, Flynn HW. In Vitro Fluoroquinolone Resistance in Staphylococcual Endophthalmitis isolates. Arch Ophthalmol. 2006; 124: 479-483. *** Montan PG, Wejde G, Setterquist H et al. Prophylactic intracameral cefuroxime. Evaluation of safety and kinetics in cataract surgery. JCRS 2002; 28: 982-987.

Intracameral moxifloxacin Moxifloxacin Dose 100 µg in 0.1cc. 300 µg in 0.2cc 500 µg in 0.1cc Final AC concentration 330 mg / L 1000 mg / L 1660 mg / L AC concentration – 1 hour 82 mg / L 250 mg / L 415 mg /L AC concentration – 2 hours 20 mg / L 62 mg / L 104 mg /L AC concentration – 3 hours 5 mg / L 16 mg / L 26 mg / L AC concentration – 4 hours 1 mg / L 4 mg / L 6.5 mg / L = < MIC of Our case; = <MIC90 Miller et al endophthalmitis resistant isolates It is clear from the above that our previous moxifloxacin dose was likely inadequate to eradicate resistant strains of Staphylococci, despite the rapid dose dependent bactericidal effect of moxifloxacin. The 500 µg/0.1 cc. (direct from the bottle of eye drops) has the disadvantage of a less physiologic solution for intracameral injection compared to the 300 µg/0.2 cc, which is a mixture of 3 cc Vigamox® from the bottle diluted with 7 cc BSS. We have therefore chosen to use 300 µg/0.2 cc as our routine, as a compromise of bactericidal efficacy and safety for the endothelium.

Does moxifloxacin have advantages over cefuroxime and vancomycin? Readily available as non-preserved eye drops (Vigamox®, Alcon). Uncomplicated to dilute. Desired dose = 150 µgm/0.1 cc. (use 0.2 cc. yielding 1 mg./ml in AC. Aspirate 3 ml Vigamox® + 7 ml BSS in 12 cc. syringe. Millipore filter not needed. Dose dependent (not time dependent bactericidal activity). Broad antibacterial spectrum of activity of moxifloxacin. Better than cefuroxime or vancomycin *Even if an infection occurs, it will likely be moxifloxacin resistant Staphylococcus, which is very sensitive to the usual endophthalmitis protocol of vancomycin and ceftazidime, whereas infections that occur with intracameral cefuroxime are often with destructive resistant bacteria , such as enterobacter. Drug allergy very rare with moxifloxacin. The risk of developing AMD can now be predicted accurately on the basis of smoking history and specific inherited genetic variations that can be measured from birth (1). Specific genetic variation in the complement factor H (2), complement component 3 (3), complement factor I (4) as well as a specific sequence variations in a locus containing the age-related maculopathy sensitivity 2 (ARMS2) gene (5) account for over 60% of the risk of developing this disease (6). Interpretive algorithms have been developed that can now accurately assign individuals to a low AMD risk category, with less than 5% life time risk of developing AMD-related visual impairment (50% of individuals), average risk (30% of individuals), and high risk groups (20% of individuals), with the most extreme having over 65% likelihood of visual impairment   1. Swaroop A, Branham KE, Chen W, Abecasis G. Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. Human Molecular Genetics. 2007;16 Spec No 2:R174-82.:R174-R82. 2. Li M, tmaca-Sonmez P, Othman M, Branham KE, Khanna R, Wade MS, et al. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. NatGenet. 2006;38(9):1049-54. 3. Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, et al. Complement C3 variant and the risk of age-related macular degeneration. NEnglJMed. 2007;357(6):553-61. 4. Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM. Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet. 2009 Jan;17(1):100-4. 5. Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, et al. Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. NatGenet. 2008;40(7):892-6. 6. Spencer KL, Olson LM, Anderson BM, Schnetz-Boutaud N, Scott WK, Gallins P, et al. C3 R102G polymorphism increases risk of age-related macular degeneration. Hum Mol Genet. 2008 Jun 15;17(12):1821-4. * Personal communication: Per Montan MD

Current anti-infective protocol – SAA Vigamox® gtts - 1 gtt q 15 min x 4 preop Betadine gtts - 5% solution 10 min preop. Betadine scrub - 10% solution prep used to paint eye preop. moxifloxacin intracameral, intracapsular at end of case. - 150µg in 0.2 cc BSS ( 1 mg/ml in AC) Vigamox® gtts - 1 gtt 6x/d x 3 days, - then QID x 7 days.

The Dose & Administration of Intracameral Moxifloxacin Conclusions: Moxifloxacin appears to offer the best option of currently available antibiotics for intracameral antibacterial prophylaxis. The optimal dose, based upon experience to date, seems to be 150 µg/0.1 cc, diluted 3:7 with balanced salt solution, with the administration of 0.2 cc intracamerally, into the capsular bag, as the final step in cataract surgery. Full Address: Dr. Steven Arshinoff 316-2155 Finch Ave. W. Toronto, Ontario, Canada ifix2is@sympatico.ca Dr. Brent Zanke MaRS Center 200-101 College St. Thank you Steve A. Arshinoff MD FRCSC Humber River Regional Hospital University of Toronto & McMaster University Email: ifix2is@sympatico.ca