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• W2270474715 abstract "Intracameral antibiotic use at the time of cataract extraction has become standard practice in Europe and is now mandated in some countries. Despite professional recognition of the potential value of intracameral antibiotics, this practice is not routine in the United States. A major barrier to adoption in the United State is the absence of a United States Food and Drug Administration (FDA)-approved intracameral antibiotic preparation. The purpose of this editorial is to highlight new research that may provide a preponderance of evidence in favor of intracameral antibiotic use and to identify the barriers to universal adoption of this practice, together with a possible solution. In this issue of Ophthalmology, 3 large observational studies from the United States (see p. 287),1Herrinton L.J. Shorstein N.H. Paschal J.F. et al.Comparative effectiveness of antibiotic prophylaxis in cataract surgery.Ophthalmology. 2016; 123: 287-294Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar India (see p. 302),2Haripriya A. Chang D.F. Namburar S. et al.Efficacy of intracameral moxifloxacin endophthalmitis prophylaxis at Aravind Eye Hospital.Ophthalmology. 2016; 123: 302-308Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar and Iran3Jabbarvand M. Hashemian H. Khodaparast M. et al.Endophthalmitis occurring after cataract surgery: outcomes of more than 480 000 cataract surgeries, epidemiologic features, and risk factors.Ophthalmology. 2016; 123: 295-301Abstract Full Text PDF PubMed Scopus (136) Google Scholar (see p. 295) involving 636 819 patients demonstrate a clear association between the use of intracameral antibiotics at the time of cataract surgery and a reduced likelihood of postoperative endophthalmitis. These findings add substantial confirmatory evidence that supports the landmark 16 000-patient European Society of Cataract and Refractive Surgeons (ESCRS) multicenter study of endophthalmitis led by Peter Barry and colleagues.4ESCRS 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; 22: 978-988Abstract Full Text Full Text PDF Scopus (649) Google Scholar These new studies together with previously published studies represent more than 1.3 million patients in whom topical antibiotics were associated with a weighted-average 2.66-fold greater incidence of postoperative endophthalmitis than were intracameral antibiotics (Table 1).5Garat M. Moser C.L. Martin Baranera M. et al.Prophylactic intracameral cefazolin after cataract surgery: endophthalmitis risk reduction and safety results in a 6 year study.J Cataract Refract Surg. 2009; 35: 637-642Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 6Romero-Aroca P. Mendez-Marin I. Salvat-Serra M. et al.Results at seven years after use of intracameral cefazolin as an endophthalmitis prophylaxis in cataract surgery.GMC Ophthalmology. 2012; 12: 2-7Crossref PubMed Scopus (33) Google Scholar, 7Tan C. Wong H.K. Yang F.P. Epidemiology of postoperative endophthalmitis in an Asian population: 11 year incidence and effect of intracameral antibiotic agents.J Cataract Refract Surg. 2012; 38: 425-430Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 8Barreau G. Mounier M. Marin B. et al.Intracameral cefuroxime injection at the end of cataract surgery to reduce the incidence of endophthalmitis: French study.J Cataract Refract Surg. 2012; 38: 1370-1375Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 9Van der Merwe J. Mustak H. Cook C. Endophthalmitis prophylaxis with intracameral cefuroxime in South Africa.J Cataract Refract Surg. 2012; 38: 2054-2059Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 10Shorstein N.H. Winthrop K.L. Herrington L.J. Decreased postoperative endophthalmitis rate after institution of intracameral antibiotics in a Northern California eye department.J Cataract Refract Surg. 2013; 39: 8-14Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 11Friling E. Lundström M. Stenevi U. Montan P. Six-year incidence of endophthalmitis after cataract surgery: Swedish national study.J Cataract Refract Surg. 2013; 39: 15-21Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 12Rodríguez-Caravaca G. García-Sáenz M.C. Villar-Del-Campo M.C. et al.Incidence of endophthalmitis and impact of prophylaxis with cefuroxime on cataract surgery.J Cataract Refract Surg. 2013; 39: 1399-1403Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 13Matsuura K. Miyoshi T. Suto C. et al.Efficacy and safety of prophylactic intracameral moxifloxacin injection in Japan.J Cataract Refract Surg. 2013; 39: 1702-1706Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 14Sharma S. Sahu S.K. Dhillon V. et al.Reevaluating intracameral cefuroxime as a prophylaxis against endophthalmitis after cataract surgery in India.J Cataract Refract Surg. 2015; 41: 393-399Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar One of the published studies14Sharma S. Sahu S.K. Dhillon V. et al.Reevaluating intracameral cefuroxime as a prophylaxis against endophthalmitis after cataract surgery in India.J Cataract Refract Surg. 2015; 41: 393-399Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar suggested a benefit of intracameral antibiotics, but failed to reach statistical significance, potentially as a function of sample size.Table 1Meta-analysis of Available Experimental and Observational Studies Related to Use of Intracameral Antibiotic ProphylaxisData for Reference 4 are based on proven cases of endophthalmitis on an intent-to-treat basis as summarized in Figure 2 (page 981) of the published study.4ESCRS 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; 22: 978-988Abstract Full Text Full Text PDF Scopus (649) Google ScholarReferenceYearTypeAntibioticWithout ICWith ICRelative Rate IC-/IC+CountryTotal NNEndophthalmitis RateNEndophthalmitis RateESCRS4ESCRS 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; 22: 978-988Abstract Full Text Full Text PDF Scopus (649) Google Scholar2007RCTCefuroxime81030.212%81080.037%5.7EU16 211Garat5Garat M. Moser C.L. Martin Baranera M. et al.Prophylactic intracameral cefazolin after cataract surgery: endophthalmitis risk reduction and safety results in a 6 year study.J Cataract Refract Surg. 2009; 35: 637-642Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar2009ObsCefazolin59300.420%12 6490.047%8.9Spain18 579Romero-Aroca6Romero-Aroca P. Mendez-Marin I. Salvat-Serra M. et al.Results at seven years after use of intracameral cefazolin as an endophthalmitis prophylaxis in cataract surgery.GMC Ophthalmology. 2012; 12: 2-7Crossref PubMed Scopus (33) Google Scholar2012ObsCefazolin11 6960.063%13 5050.050%1.3Spain25 201Tan7Tan C. Wong H.K. Yang F.P. Epidemiology of postoperative endophthalmitis in an Asian population: 11 year incidence and effect of intracameral antibiotic agents.J Cataract Refract Surg. 2012; 38: 425-430Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar2012ObsCefazolin29 5390.064%20 6380.010%6.4Singapore50 177Barreau8Barreau G. Mounier M. Marin B. et al.Intracameral cefuroxime injection at the end of cataract surgery to reduce the incidence of endophthalmitis: French study.J Cataract Refract Surg. 2012; 38: 1370-1375Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar2012ObsCefuroxime28261.230%22890.044%28.0France5115Vand der Merwe9Van der Merwe J. Mustak H. Cook C. Endophthalmitis prophylaxis with intracameral cefuroxime in South Africa.J Cataract Refract Surg. 2012; 38: 2054-2059Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar2012ObsCefuroxime42190.550%39710.080%6.9S. Africa8190Shorstein10Shorstein N.H. Winthrop K.L. Herrington L.J. Decreased postoperative endophthalmitis rate after institution of intracameral antibiotics in a Northern California eye department.J Cataract Refract Surg. 2013; 39: 8-14Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar2013Obsseveral28780.300%13 3860.070%4.3California16 264Friling11Friling E. Lundström M. Stenevi U. Montan P. Six-year incidence of endophthalmitis after cataract surgery: Swedish national study.J Cataract Refract Surg. 2013; 39: 15-21Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar2013Obsseveral28040.390%461 9510.027%14.4Sweden464 755Rodriguez12Rodríguez-Caravaca G. García-Sáenz M.C. Villar-Del-Campo M.C. et al.Incidence of endophthalmitis and impact of prophylaxis with cefuroxime on cataract surgery.J Cataract Refract Surg. 2013; 39: 1399-1403Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar2013ObsCefuroxime65950.590%12 8680.039%15.1Spain19 463Matsuura13Matsuura K. Miyoshi T. Suto C. et al.Efficacy and safety of prophylactic intracameral moxifloxacin injection in Japan.J Cataract Refract Surg. 2013; 39: 1702-1706Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar2013ObsMoxiflocacin15 9580.050%18 7940.010%5.0Japan34 752Sharma14Sharma S. Sahu S.K. Dhillon V. et al.Reevaluating intracameral cefuroxime as a prophylaxis against endophthalmitis after cataract surgery in India.J Cataract Refract Surg. 2015; 41: 393-399Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar2015RCTCefuroxime77560.155%73660.108%1.4India15 122Haripriya2Haripriya A. Chang D.F. Namburar S. et al.Efficacy of intracameral moxifloxacin endophthalmitis prophylaxis at Aravind Eye Hospital.Ophthalmology. 2016; 123: 302-308Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar2016ObsMoxifloxacin78 5540.075%38 1600.020%3.8India116 714Herrinton1Herrinton L.J. Shorstein N.H. Paschal J.F. et al.Comparative effectiveness of antibiotic prophylaxis in cataract surgery.Ophthalmology. 2016; 123: 287-294Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar2016ObsCefazolin237 6950.070%63 0490.044%1.6USA300 745Hashemian3Jabbarvand M. Hashemian H. Khodaparast M. et al.Endophthalmitis occurring after cataract surgery: outcomes of more than 480 000 cataract surgeries, epidemiologic features, and risk factors.Ophthalmology. 2016; 123: 295-301Abstract Full Text PDF PubMed Scopus (136) Google Scholar2016ObsCefuroxime193 4400.014%25 9200∞Iran219 360Totals (weighted average)607 9930.075%702 6540.028%2.661 310 648Obs = observational study; RCT = randomized controlled trial. Open table in a new tab Obs = observational study; RCT = randomized controlled trial. Longitudinal rates of endophthalmitis in the United States were first reported from 1984 national data15Javitt J.C. Vitale S. Canner J.K. et al.National outcomes of cataract extraction: endophthalmitis following inpatient surgery.Arch Ophthalmol. 1991; 109: 1085-1089Crossref PubMed Scopus (230) Google Scholar and have been updated periodically as cataract surgical technique has evolved.16Javitt J.C. Street D.A. Tielsch J.M. et al.Cataract Patient Outcomes Research Team. National outcomes of cataract extraction: retinal detachment and endophthalmitis after outpatient cataract surgery.Ophthalmology. 1994; 101: 100-105Abstract Full Text PDF PubMed Scopus (167) Google Scholar, 17West E.S. Behrens A. McDonnell P.J. et al.The incidence of endophthalmitis after cataract surgery among the U.S. Medicare population increased between 1994 and 2001.Ophthalmology. 2005; 112: 1388-1394Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar The most recent analysis, drawn from 2010 through 2014 Medicare data and presented in Coleman's18Coleman A.L. How big data informs us about cataract surgery: The LXXII Edward Jackson Memorial Lecture.Am J Ophthalmol. 2015; 160: 1091-1103Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar 2015 Jackson Memorial Lecture identified a rate of 1.2 per 1000, which is essentially unchanged since 1994. Coleman's analysis also includes the American Academy of Ophthalmology Intelligent Research in Sight (IRIS) database, which captures data from office-based electronic medical record systems and records a lower (0.7/1000) rate of endophthalmitis. Although IRIS has the advantage of capturing laterality, which the Medicare dataset does not, it is not yet representative of all United States ophthalmologists and does not yet have a mechanism for ascertaining patients with endophthalmitis who do not seek treatment at the office of the original cataract surgeon. Internationally reported estimates of the incidence of endophthalmitis without intracameral antibiotics vary, with rates reported as high as 12 per 1000 cataract procedures8Barreau G. Mounier M. Marin B. et al.Intracameral cefuroxime injection at the end of cataract surgery to reduce the incidence of endophthalmitis: French study.J Cataract Refract Surg. 2012; 38: 1370-1375Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar and as low as 0.5 per 100013Matsuura K. Miyoshi T. Suto C. et al.Efficacy and safety of prophylactic intracameral moxifloxacin injection in Japan.J Cataract Refract Surg. 2013; 39: 1702-1706Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar over a several-year period. Thus, critics of applying the European Union experience to the United States are correct in noting that the baseline rate of endophthalmitis in the United States is substantially lower than the rate reported from many other localities. However, Herrinton et al1Herrinton L.J. Shorstein N.H. Paschal J.F. et al.Comparative effectiveness of antibiotic prophylaxis in cataract surgery.Ophthalmology. 2016; 123: 287-294Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar demonstrate in this issue that even with a baseline rate of endophthalmitis in their Accountable Care Organization (0.07%) that is considerably lower than the national average, there is room for incremental improvement with intracameral antibiotics. Before addressing the challenges associated with implementing universal adoption of these findings, it is critical to note that the increased risk of infection seen with use of topical antibiotics alone is smaller than the increased risk associated with vitreous loss and retained lens fragments, as is also highlighted in this edition of Ophthalmology19Hahn P. Yashkin A.P. Sloan F.A. Effect of prior anti-VEGF injections on the risk of retained lens fragments and endophthalmitis after cataract surgery in the elderly.Ophthalmology. 2016; 123: 309-315Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar (see pg. 309) and as has been reported previously from national databases.1Herrinton L.J. Shorstein N.H. Paschal J.F. et al.Comparative effectiveness of antibiotic prophylaxis in cataract surgery.Ophthalmology. 2016; 123: 287-294Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 2Haripriya A. Chang D.F. Namburar S. et al.Efficacy of intracameral moxifloxacin endophthalmitis prophylaxis at Aravind Eye Hospital.Ophthalmology. 2016; 123: 302-308Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar The combination of surgeon experience and surgeon volume is associated with a 5-fold difference in the risk of endophthalmitis across the spectrum of highest to lowest volume surgeons. This may be linked inextricably to the incidence of vitreous loss.9Van der Merwe J. Mustak H. Cook C. Endophthalmitis prophylaxis with intracameral cefuroxime in South Africa.J Cataract Refract Surg. 2012; 38: 2054-2059Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar The use of intracameral antibiotics has been recognized by the Preferred Practice Pattern of the American Academy of Ophthalmology, which states that “there is mounting evidence that injecting intracameral antibiotics is an efficacious method of endophthalmitis prophylaxis.”20American Academy of Ophthalmology Cataract and Anterior Segment Panel Preferred Practice Pattern Guidelines. Cataract in the Adult Eye. American Academy of Ophthalmology, San Francisco, CA2011: 19-20Google Scholar Even so, topical antibiotic prophylaxis remains common in the United States, whereas it has nearly vanished in Europe. In Sweden it has become universal practice. In France and Denmark, where a commercial intracameral antibiotic product is available, the governmental authorities supported by the national ophthalmological societies have specifically recommended intracameral antibiotic use as a national standard of care. In Spain, the Supreme Court found a physician negligent for failure to use intracameral prophylaxis.21Supreme Court of Justice, Madrid, Spain. Court ruling 4193/2010. June 28, 2010.Google Scholar Commercially formulated intracameral antibiotics may be associated with new risks to patients; however, none of the cited studies has identified such risks. The recent editorial by Schimel et al22Schimel A.M. Alfonso E.C. Flynn Jr., H.W. Endophthalmitis prophylaxis for cataract surgery: are intracameral antibiotics necessary?.JAMA Ophthalmol. 2014; 132: 1269-1270Crossref PubMed Scopus (25) Google Scholar questioning the appropriateness of intracameral antibiotic use in the United States largely focused on the risks of improper and ad hoc formulation and did not identify any proven risks associated with using commercially formulated intracameral antibiotics. The editorial mentioned the potential for allergic reactions, which can be seen with both topical and intracameral antibiotics and toxic reactions and which have not been reported in Europe since the introduction of a commercially manufactured intracameral formulation. However, as noted by Schimel et al, we should remain vigilant for the possibility that intracameral antibiotics promote antibiotic resistance in a way that topical antibiotics do not and for the possibility that endophthalmitis, when it does follow intracameral use, is more aggressive than it is after topical antibiotic use. In the absence of a commercial formulation, American ophthalmologists who wish to offer intracameral antibiotics to their patients have the option of procuring antibiotics that have been compounded in a United States Pharmacopeial Convention (USP)-compliant manner in response to a patient-specific prescription. This option should be considered particularly for patients at increased risk for infection, such as those who have had repeated anti-vascular endothelial growth factor (VEGF) injections, as documented elsewhere in this issue. In no way should this editorial encourage the adoption of ad hoc compounding practices by physicians or operating room personnel under their direction. Custom compounding of drugs is regulated by state law. Although many states allow physicians, as well as pharmacists, to perform such activities, state laws explicitly require or imply that such activities will comply with the USP, which sets standards for documentation, sterility, particulate control, and so forth, that are unlikely to be met by any physician mixing up antibiotics intended for intravenous use in the operating room. Indeed, the reported complications attributed to intracameral antibiotics primarily have been attributed to errors in diluent, dilution, and dosing and to failures of sterility. The mixing of cefuroxime intended for intravenous use with balanced salt solution creates a myriad of risks that are magnified if the vial containing cefuroxime then is punctured multiple times for use in multiple patients. The risk is even higher if ordinary intravenous saline from a bag is used. Moreover, the quantity and size of latex particles generated by this practice is certain to breach the ophthalmic particulate standard outlined in the USP. Safe, USP-compliant formulation involves quality control of the environment where the mixing occurs, often with the use of laminar flow hoods, micropore filters, and other resources not generally found in the operating room environment. Based on the combined results of these and other studies summarized in Table 1, at a current rate of 3 million cataract surgeries per year in the United States, there is a potential to save more than 2000 eyes per year from the negative impact of postoperative endophthalmitis. However, this potentially sight-saving change in practice is unlikely to be adopted broadly in the absence of an FDA-approved commercial antibiotic formulation. Because of statutory differences between United States and European drug law, and because of the law and regulations that bar the FDA's Division of Transplant and Ophthalmology Products from a routine product approval, a creative partnership between our profession and the FDA may be required to bring such a formulation to market. The use of intracameral antibiotics to prevent postoperative infection after cataract and other intraocular surgery was proposed first by Montan et al23Montan P.G. Wejde G. Koranyi G. Rylander M. Prophylactic intracameral cefuroxime: efficacy in preventing endophthalmitis after cataract surgery.J Cataract Refract Surg. 2002; 28: 977-981Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar in 2002. Over the subsequent decades, the ad hoc formulation and intracameral injection of antibiotics packaged and labeled for intravenous use became popular in certain centers. The advocates of this practice, together with their detractors, motivated the ESCRS to raise the funds needed to conduct a randomized prospective study of intracameral versus topical antibiotic prophylaxis at 24 centers across Europe. Although the study planned to enroll 35 000 patients in order to meet its sample size projections for statistical significance, the study was stopped in 2006 after an interim analysis of the first 16 000 patients demonstrated a 4.92-fold increase (95% confidence interval, 1.87–12.9) in the risk of postoperative endophthalmitis associated with topical versus intracameral antibiotic prophylaxis. As a result of these findings, the use of intracameral antibiotics began to rise in Europe, despite the lack of an approved intracameral formulation. Physicians were forced to rely on formulations of intravenous antibiotics sometimes prepared by well-qualified pharmacies, but all too often mixed ad hoc in the operating theater. Because of the widespread professional demand for a safe, easy-to-administer intracameral antibiotic preparation and because the ESCRS study qualified as a valid efficacy study under European law, a commercial manufacturer was able to formulate and obtain a license to market a single-use preparation of cefuroxime, labeled for intraocular use. It should be recognized that the purity and particulate standards of preparations for use inside the eye, outlined by the USP and the FDA, are much stricter than the standards required for formulations labeled for intravenous use.24United States Pharmacopeia and National FormularyParticulate Matter in Ophthalmic Solutions. USP 789. United States Pharmacopeia and National Formulary, Rockville, MD2015Google Scholar Commercially prepared intraocular cefuroxime has been met with widespread acceptance across the European Union. Interestingly, it is priced substantially below the price of topical antibiotic eye drops. Although one might have expected a similar change in clinical practice in the United States, a key limitation to adoption in the United States is the lack of an FDA-approved antibiotic formulation for intracameral use. United States ophthalmologists are thus dissuaded from the use of intracameral antibiotics by the risk, liability, and financial, legal, and logistical challenges of using unapproved antibiotic formulations. The risks of ad hoc compounding of antibiotic mixtures in the operating room is fraught with peril, as discussed above. Although there are licensed pharmacies capable of delivering custom-compounded sterile products, pharmacies are expected to provide drug products only in response to a patient-specific prescription or order that must be written for each dose of intracameral antibiotic that a surgeon plans to use. Recent FDA inspections of 28 pharmacies known to be formulating prescriptions for sterile medications identified violations of the Food Drug and Cosmetic Act by all 28 pharmacies.25United States Food and Drug Administration. Summary: 2013 FDA Pharmacy Inspection Assignment. Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm347722.htm. Accessed November 1, 2015.Google Scholar The FDA has reminded pharmacies that bulk shipping of compounded medications in the absence of a patient-specific prescription is outside the customary practice of the pharmacy and enters the realm of manufacture. Although the position of the FDA is that it does not intend to discourage compounding that is conducted in compliance with state pharmacy laws, the FDA website explicitly states that in 4 cases, the FDA inspectors were accompanied by armed United States marshals. Based on the experience in Europe, there is little likelihood that adoption of intracameral antibiotic use will increase in the United States absent the availability of an FDA-approved commercially formulated intracameral antibiotic preparation. To avoid potentially 2000 cases of endophthalmitis per year in the United States and potentially to do the right thing for our patients, 3 key barriers must be overcome. The first and most obvious barrier is that to the best of anyone's knowledge, no commercial sponsor has submitted a New Drug Application (NDA) to the FDA for such a product. Thus, although it is always easy to blame the FDA for a lack of progress in medical science, there is little the FDA can do in the absence of an application. The FDA would be expected to have a high degree of motivation to support the approval of an intracameral antibiotic should one be shown to be safe and effective. The second barrier, which may be the primary reason no commercial sponsor seems to have applied to the FDA either to test or to market an intracameral antibiotic formulation, is that the likely economic return is minimal. All of the antibiotics that so far have shown themselves to be effective for prevention of endophthalmitis (primarily cefuroxime) are generic molecules around which no obvious form of patent protection can be obtained. Antibiotics fall into a category (section 507) of the Food, Drug, and Cosmetic Act in which no period of market exclusivity is awarded for newly granted drug approvals. Thus, the first product manufacturer to invest the resources to bring an intracameral antibiotic to market likely would obtain no legal barrier to competition. The third barrier is regulatory. The United States Food and Drug law requires “adequate and well-controlled investigations” demonstrating safety and efficacy as a precondition to granting approval to market a drug in the United States. Such studies must be performed with the actual drug product that a manufacturer intends to market. The term adequate and well-controlled investigations has other very specific definitions delineated in the United States Code of Federal Regulations (21CFR314.126). Although the ESCRS study was a landmark and the largest randomized controlled trial ever performed in ophthalmology, it was not performed with a commercially formulated antibiotic preparation that any manufacturer is proposing to launch in the United States. Moreover, the ESCRS study is unlikely to meet the usual standard of adequate and well-controlled investigations from the FDA perspective, although it was fully compliant with EU standards. The personal opinions of FDA staff regarding the merits and limitations of the study have been presented at past American Academy of Ophthalmology meetings and elsewhere (Chambers W, personal communication, 2015). Among the limitations are (1) the rate of endophthalmitis in the study control group was far higher than expected and far exceeded the rate in European Union observational studies, artificially boosting the study power; (2) the potential for bias resulting from the treatment arms being unmasked; (3) the multiple looks taken at the data without an adjustment in the P value to account for the possibility of a false-positive finding; (4) the analysis that underlying the early termination of the trial involved the combination of multiple subgroups in a post hoc manner, a practice that introduces potential bias in the results; and (5) the low number of incident cases. Based on these limitations, the FDA normally would expect another randomized trial, performed with the candidate commercially manufactured drug product, to demonstrate a statistically significant reduction in the rate of endophthalmitis to support an NDA. The European randomized clinical trial experience has demonstrated amply that one must be prepared to enroll 35 000 patients to complete such a trial. There are potential ethical concerns associated with conducting such a randomized clinical trial in light of substantial existing evidence that demonstrates the superiority of intracameral antibiotic use. Physicians who believe this evidence may perceive a lack of equipoise between the groups being studied, raising an ethical bar to participation. That is, it is not ethical to perform a human study simply to prove to a higher standard something that the physician already believes has been proven. Human subjects committees similarly may raise ethical concerns, given the preponderance of the data and overseas regulatory findings in favor of intracameral antibiotics. Lastly, any patient brochure must present the totality of the data as outlined in Table 1, which may dissuade many patients from enrolling as study subjects and motivate them to request intracameral antibiotics under a pharmacy prescription instead. Indeed, it would likely be unethical to deny patients this choice, because formulated intracameral antibiotics are available legally without an experimental protocol, unlike the situation in many clinical trials where the study drug is only available to patients who enroll in the study. In addition to the potential ethical barriers, there is a substantial commercial barrier to the implementation of an adequate pivotal study. The costs of study design, monitoring, and analysis, along with fees paid to investigators and facilities, combined with the costs of study drug and other costs associated with FDA-mandated Good Manufacturing Practices compliance, likely exceeds $10 000 per patient. That is, the sponsor of a trial must be willing to spend $350 million and expect a negative return on its investment. There is not much chance of any commercial sponsor making an investment like that without suffering the wrath of its shareholders. This impasse leaves American ophthalmologists with a conundrum in which the majority of the data supports a change in practice that is blocked by current financial and regulatory mechanisms. Those who choose to use intracameral antibiotics must absorb the inconvenience and liability associated with a legal but unapproved drug product. The evidence published in this edition of Ophthalmology, together with prior studies, suggests that those who do not use intracameral antibiotics may subject their patients to an increased risk of endophthalmitis, along with the inconvenience of multiple daily drops for weeks after surgery. A complete cost-effectiveness evaluation, which would need to consider the economic outcomes associated with vision loss from endophthalmitis, is beyond the scope of this editorial. However, it is not clear that intracameral antibiotics cost more than some of the currently prescribed topical antibiotics used today. If intracameral antibiotics are price neutral versus topical antibiotics, and if there is a 73% reduction in risk associated with intracameral prophylaxis, the shift to intracameral use actually could be cost saving. Naturally, a formal analysis also would consider the costs and disutility associated with vitrectomy, vision loss, or both associated with endophthalmitis. Fortunately, there are 2 possible regulatory paths that may provide a solution to this conundrum. The law (21CFR314.126(b)(2)(v)) does provide for situations in which the FDA may allow historical controls to demonstrate efficacy in exceptional circumstances where randomized prospective studies are simply infeasible. Thus, the newly published reports of 637 000 patients that confirm the ESCRS trial and prior published studies may be deemed by the FDA as sufficient. Failing that, the CFR states: “The Director of the Center for Drug Evaluation and Research may, on the Director's own initiative or on the petition of an interested person, waive in whole or in part any of the criteria in paragraph (b) of this section with respect to a specific clinical investigation, either prior to the investigation or in the evaluation of a completed study.” Thus, although most FDA officials are bound to follow the requirements for adequate and well-controlled studies as articulated by 314.126, the director of Center for Drug Evaluation and Research has broad discretion to waive those requirements in the public interest. Naturally, such an approach is likely to be successful only with strong professional and public support. Outside of the approval of drugs to treat lethal or permanently disabling toxic biological, chemical, radiologic, or nuclear substances, there is relatively little precedent in the modern era for the agency waive the need for adequate and well-controlled studies to support a new drug application. If the newly published data in this issue suggest to the profession that a change in practice is warranted, the logical sequence of events must be as follows. The American Academy of Ophthalmology and the American Society of Cataract and Refractive Surgeons must gather the preponderance of data in support of intracameral antibiotic use and request that the FDA's Division of Transplant and Ophthalmology Products convene a meeting of the Dermatology and Ophthalmology Advisory Committee to review the material and advise the agency as to (1) whether the current bulk of data is sufficient to justify the use of historic controls in lieu of a randomized pivotal study or (2) whether a waiver should be sought from the director of Center for Drug Evaluation and Research authorizing approval of an intracameral antibiotic preparation in the absence of “adequate and well-controlled investigations.” The advisory panel should be careful to broadly solicit all available input and testimony for and against the request for a waiver. Thus far, no person or organization has argued against the use of intracameral antibiotics if properly and safely formulated to commercial standards, although Schimel et al22Schimel A.M. Alfonso E.C. Flynn Jr., H.W. Endophthalmitis prophylaxis for cataract surgery: are intracameral antibiotics necessary?.JAMA Ophthalmol. 2014; 132: 1269-1270Crossref PubMed Scopus (25) Google Scholar argue that perhaps commercially formulated intracameral antibiotics ought be reserved for high-risk cases and for areas with higher than normal rates of endophthalmitis. If the Advisory Committee recommends the adoption of historical data, the FDA has the regulatory discretion to accept the recommendation. If the Advisory Committee recommends that a waiver be sought, the professional organizations that represent us and our patients should petition for such a waiver as rapidly as is practical. Such a petition must articulate clearly why the CFR criteria are not reasonably applicable to the case of intracameral antibiotics, what alternative procedures—if any—are to be or have been used, and what results have been obtained. The petition also must state why the clinical investigations so conducted will yield, or have yielded, substantial evidence of effectiveness, notwithstanding nonconformance with the CFR criteria for which waiver is requested. The above-proposed path still does not solve the problem of motivating a commercial entity to supply properly manufactured intracameral antibiotics. However, if the FDA regulatory hurdle is lowered to the point where a commercial sponsor merely needs to prove safety of the product and compliance with good manufacturing practices, rather than efficacy of the product in preventing endophthalmitis, it is likely that commercial entrants will emerge. The data published in this edition of Ophthalmology make a strong case for universal adoption of intracameral antibiotic prophylaxis after cataract surgery and, by extension, other forms of intraocular surgery. This practice already has been adopted in Europe and elsewhere. The challenge is for the ophthalmology community and FDA to join forces to offer the best possible care to our patients. The author thanks Dr. Peter Barry, FRCS, FRCOphth, FRCSI, for sharing his historical perspective and encyclopedic knowledge. Effect of Prior Anti–VEGF Injections on the Risk of Retained Lens Fragments and Endophthalmitis after Cataract Surgery in the ElderlyOphthalmologyVol. 123Issue 2PreviewTo investigate the effect of prior intravitreal anti–vascular endothelial growth factor (VEGF) injections on surgical and postoperative complication rates associated with cataract surgery in a nationally representative longitudinal sample of elderly persons. Full-Text PDF Retraction notice to: Endophthalmitis Occurring after Cataract Surgery: Outcomes of More Than 480 000 Cataract Surgeries, Epidemiologic Features, and Risk FactorsOphthalmologyVol. 123Issue 2PreviewThis article has been retracted: please see Elsevier policy on Article Withdrawal ( https://www.elsevier.com/about/ourbusiness/policies/article-withdrawal ). The editors wish to note that concerns were raised regarding coding errors in the data set that formed the basis of this study. Patient record numbers were found to be duplicated, so that the number of endophthalmitis cases was unclear as was the associated treatment, and the number of unique patients estimated to be far less than the 480,000 reported. Full-Text PDF Comparative Effectiveness of Antibiotic Prophylaxis in Cataract SurgeryOphthalmologyVol. 123Issue 2PreviewIntracameral injection is an effective method for preventing infection, but no controlled study has been published in the United States. Full-Text PDF Efficacy of Intracameral Moxifloxacin Endophthalmitis Prophylaxis at Aravind Eye HospitalOphthalmologyVol. 123Issue 2PreviewTo compare the rate of postoperative endophthalmitis before and after initiation of intracameral (IC) moxifloxacin for endophthalmitis prophylaxis in patients undergoing cataract surgery. Full-Text PDF Re: Javitt JC: Intracameral antibiotics reduce the risk of endophthalmitis after cataract surgery: does the preponderance of the evidence mandate a global change in practice? (Ophthalmology 2016;123:226-231)OphthalmologyVol. 124Issue 1PreviewThe editorial by Javitt1 is a remarkable turnaround from the editorial in Ophthalmology on the same subject in 2007.2 Full-Text PDF Re: Javitt JC: Intracameral antibiotics reduce the risk of endophthalmitis after cataract surgery: does the preponderance of the evidence mandate a global change in practice? (Ophthalmology 2016;123:226-231)OphthalmologyVol. 124Issue 1PreviewI read the paper by Javitt1 with interest; however, I believe that some discussion is mandatory. Full-Text PDF" @default.
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