REVIEW

The Routine Use of Intracameral Antibiotics to PreventEndophthalmitis After Cataract Surgery: How Good isthe Evidence?

Nicholas K. George . Michael W. Stewart

Received: June 11, 2018 / Published online: July 5, 2018� The Author(s) 2018

ABSTRACT

Post-operative endophthalmitis (POE) followingcataract surgery is an uncommon, vision-threatening complication that has been repor-ted to occur at rates of between approximately0.03% and 0.2%. Prompt diagnosis and treat-ment of endophthalmitis is critical for mini-mizing vision loss, but most recent efforts havefocused on the prophylactic administration ofantibiotics to prevent the development ofendophthalmitis. Surgeons from around theworld have different topical and intracameralantibiotic usage patterns to prevent endoph-thalmitis, and to date no general consensusregarding best practice has emerged. Severalstudies have reported on the routine use ofintracameral cefuroxime, moxifloxacin, andvancomycin, including a single randomizedclinical trial by the European Society of Cataractand Refractive Surgery (ESCRS) in 2007. Thesestudies have notable shortcomings, but many

authors suggest that intracameral cefuroximetogether with topical antibiotics probablydecreases the risk of endophthalmitis. However,the deleterious effects of routine prophylacticantibiotics, which include toxicity, cost, andincreasing antimicrobial resistance, amongothers, are noteworthy. In contrast, aseptictechnique with pre-operative instillation ofpovidone-iodine remains the only techniquesupported by level I evidence to reduce theincidence of endophthalmitis. Although theroutine use of intracameral antibiotics contin-ues to increase throughout the world, data frommulticenter, randomized, prospective trials isneeded to provide better guidance regarding theprophylactic use of antibiotics.

Keywords: Cataract surgery; Cefuroxime;Endophthalmitis; Intracameral; Moxifloxacin;Vancomycin

INTRODUCTION

Cataract extraction with intraocular lensimplantation is the most frequently performedsurgery throughout the world, with more than10 million cases completed each year. Mostpatients experience uncomplicated post-opera-tive courses and their visual acuities usuallyimprove. With advances in surgical instrumen-tation, techniques, and training, the incidences

Enhanced digital features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.6683093.

N. K. GeorgeUniversity of Colorado School of Medicine, Aurora,CO, USA

M. W. Stewart (&)Department of Ophthalmology, Mayo Clinic,Jacksonville, FL, USAe-mail: Stewart.michael@mayo.edu

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https://doi.org/10.1007/s40123-018-0138-6

of significant post-operative problems are, for-tunately, very low.

One of the most feared complications ofcataract surgery, however, remains endoph-thalmitis. Post-operative endophthalmitis canbe defined as ‘‘severe inflammation involvingboth the anterior and posterior segments of theeye after intraocular surgery’’ [1]. It usually fol-lows inoculation of the eye by bacteria, withfungi and parasites being less commonlyinvolved, and has been reported to occur atrates of between 0.03% and 0.2% [2]. Endoph-thalmitis can have devastating effects on vision,with final acuities ranging from normal tocomplete loss in the affected eye. Unfortu-nately, the prognosis is frequently poor, and itdepends on several factors, including the cau-sative organism and time to diagnosis.

Incidence rates of post-operative endoph-thalmitis (POE) have fluctuated in conjunctionwith changes in surgical techniques, but theyhave generally been stable over the past two dec-ades. Some authors have opined that endoph-thalmitis shouldbe a ‘‘never event’’ [3], butwe stillknow too little about the associated risk factors tostate that we can completely eradicate POE [4, 5].Nonetheless, physicians continuously attempt todecrease the incidence of endophthalmitis byapplying innovative aseptic and surgical tech-niques. Most surgeons believe that endoph-thalmitis rates can continue to be improved, evenbeyond a baseline endophthalmitis rate of 0.07%,which is significantly lower than any nation’sreported average to date [6].

Here we describe current attempts to reducethe incidence of post-cataract extractionendophthalmitis and provide our own recom-mendations that are based upon a review of theliterature and our own institution’s aseptictechniques. This article is based on previouslyconducted studies and does not contain anystudies with human participants or animalsperformed by any of the authors.

EVOLUTION OF CATARACTSURGERY

Cataract extraction dates back to the 17th cen-tury B.C. at which time the ‘‘couching’’

technique was used to posteriorly sublux thecataractous lens into the vitreous cavity with ablunt instrument [7]. Despite the widespreadadoption of modern surgical techniques,couching continues to be used in some parts ofthe world that have limited provision ofhealthcare. Not surprisingly, blindness ratesafter couching may be as high as 70% because ofnumerous complications, including high ratesof infection [8–10]. Reported endophthalmitisrates following couching have ranged from12.5% to 22% [10–12], but accurate rates aredifficult to verify given the relative rarity ofcouching.

Extracapsular cataract extraction through acorneal incision was first performed in 1787 byJacques Daviel after attempts to dislocate thelens during a couching procedure were unsuc-cessful. He presented this method to the RoyalAcademy of Surgery, after which his techniquegained popularity and became the new standardin place of couching [13]. Because antisepsis wasnot practiced at that time and sutures were notavailable until 1867, the corneal incisionremained open and represented a significantrisk of wound dehiscence and infection [14].Patients recovered in a dark room for approxi-mately 1 week during which the eyes werebathed with mixtures of water and wine andbandaged with a cotton dressing [15].

Phacoemulsification was introduced in 1967by Charles Kelman, after he took cues from hisdentist’s ultrasound probes. During subsequentyears, the surgical incisions became increasinglysmaller, varying from 3 mm to as small as1 mm, and together with improved instrumen-tation, the small incisions resulted in markedlyreduced inflammation after extraction of thelens [16]. Hospital stays were shortened, andeventually the surgery became an outpatientprocedure. Initially, the introduction of pha-coemulsification and sutureless clear cornealincisions led to an increase in endophthalmitisrates, from 0.074% to 0.087% up to0.0189–0.265%, which was thought to be due toincreased microbial access to the anteriorchamber after completion of the surgery [17].The clear corneal incision, however, remainsthe favored approach for cataract extraction(compared to the scleral tunnel incision) since

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it has led to faster visual recovery, shorter sur-gical times, and less manipulation of the globe.In previous surveys, clear corneal incisions werepreferred by 75% of American Society of Catar-act and Refractive Surgery (ASCRS) members[18, 19].

Femtosecond laser-assisted cataract surgery(FLACS) was introduced in 2012 after the laserhad originally been developed for refractivesurgery (laser in situ keratomileusis [LASIK] in2001). The laser automates the performance ofincisions and softens the lens nucleus, all ofwhich may improve surgical precision, accu-racy, and reproducibility. One study reportedsignificantly better optical quality and internalaberrations compared to phacoemulsification,but without significant differences in refractiveerrors or best corrected distance visual activity[20]. Whether the FLACS incisions result inlower rates of endophthalmitis is still underinvestigation [21].

PRE-OPERATIVE CARE

The antiseptic properties of iodine were firstnoted in 1811, although its high toxicity profileand low solubility originally limited its oph-thalmic application. Argyrol, a compound ofmild silver-containing proteins, was the domi-nant ophthalmic antiseptic from its commercialintroduction in 1901 until it was demonstratedto have minimal bactericidal effect in a 1983study, after which its use was gradually aban-doned [22]. The following year, a study vali-dated the effectiveness of the povidone-iodinesolution, which had originally been introducedin the 1950s as a pre-operative preparation. Thisstudy found that povidone-iodine decreased thenumber of bacterial colonies on the surface ofthe eye by 91% and the number of species by50% [23]. The benefits of povidone-iodinesolutions include rapid bactericidal action, lowtoxicity, higher solubility compared to iodinealone, and lack of bacterial resistance [24]. Theefficacy of 5–10% povidone-iodine applied tothe cornea, conjunctiva, and eyelids for at least3 min prior to surgery is supported by level Ievidence, and this procedure is now consideredstandard of care [5, 25]. The pre-operative

preparation of the eye also includes the place-ment of a sterile eyelid speculum and draping ofthe patient with isolation of the eyelids andeyelashes. Trimming of the eyelashes pre-oper-atively has no demonstrable effect on prevent-ing endophthalmitis [26].

The pre-operative administration of topicalantibiotics is relatively common—90% ofresponders to the 2014 ASCRS survey reportedroutinely using antibiotics peri-operatively [27].There is no universally agreed upon regimen,and the most common medication according tothe ASCRS survey was a topical fourth-genera-tion fluoroquinolone, such as moxifloxacin orgatifloxacin. Worldwide, fourth-generation flu-oroquinolones are the most commonly usedtopical antibiotics [28] while the less commonlyused antibiotics include the early-generationfluoroquinolones, trimethoprim-polymyxin B,gentamicin, and tobramycin. Although amino-glycosides are inexpensive and effective againstStaphylococcus spp., they do not penetrate wellinto the anterior chamber and thus comparepoorly to other choices [6]. Evidence that rou-tine use of topical antibiotics may select forresistant bacteria calls into question the wisdomof routine antibiotic use [25, 29]. Up to 90% ofcataract surgery patients, particularly thoseinexperienced with the use of eye drops,demonstrate poor instillation technique,including failure to wash hands, contaminationof bottle tips, frequent missing of the eye, dif-ficulty in extending their necks, and use of anincorrect number of drops [30]. Various instil-lation aids have been developed, and these mayameliorate at least a few of the difficulties [31].Another purported reason for nonadherence is‘‘drop phobia,’’ the reluctance to instill dropsonto the eye [32]. A 2017 systematic reviewfound ‘‘moderate-certainty evidence’’ that usingantibiotic eye drops in addition to antibioticinjections probably lowers the incidence ofendophthalmitis compared with using eitherinjections or eye drops alone [33].

INTRA-OPERATIVE CARE

Injecting intracameral antibiotics at the com-pletion of cataract surgery has become an

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increasingly popular topic of discussion sincethe European Society of Cataract and RefractorySurgeons (ESCRS) conducted a landmark ran-domized clinical trial that evaluated the routineuse of topical and intracameral antibiotics forcataract surgery in 2005. Their study included13,698 patients from 24 European centers. Pro-phylactic intracameral injections of cefuroximewas found to reduce the incidence of POE bynearly fivefold (0.33% vs. 0.07%). Critics of thisstudy have cited an unusually high rate ofendophthalmitis in the control group at 0.33%(the high end of the incidence range oftenreported in prior studies is 0.2%), the use ofmultiple surgical techniques, the narrow spec-trum of cefuroxime activity (which is not idealfor members of genus Staphylococcus), thereconstitution of the antibiotic from powder,and that the study was stopped prematurely[34].

Following publication of the ESCRS trial,many other studies from 2014 onwards, pre-dominantly retrospective in design, also sup-ported the use of intracameral antibiotics. Oneof the problems common to most of these ret-rospective studies is that they do not accountfor improvements in asepsis and operativetechniques during the same study periods,which may account for the decline in rates ofendophthalmitis. A less obvious limitation ofdatabase studies includes inaccuracies in diag-nosis and procedure coding, particularly withthe use of different International Classificationof Disease, Tenth Edition (ICD-10) codes, suchas the H44.0 codes for ‘‘purulent endoph-thalmitis’’ and H44.1 codes for ‘‘other endoph-thalmitis.’’ A relatively minor inaccuracy incoding may inadvertently exclude many casesfrom the population being studied [35, 36]. InAustralia, patients with POE were treated asoutpatients without a diagnosis entered into thedatabase being studied [37]. It is thereforeimportant to remember that big data is good atdetecting associations, but it cannot tell uswhich associations are meaningful. Big data canwork well as an adjunct to scientific inquiry, butit rarely succeeds as a wholesale replacement[38].

Around the world, the general trend hasbeen toward increasing routine use of

intracameral antibiotics. According to the 2014ASCRS survey, approximately 47% of U.S. cat-aract surgeons currently use or planned to adoptthe routine use of intracameral prophylaxis,which is up from 30% in 2007. Of thoseresponding to the survey, 69% answered thatthey would use an intracameral antibiotic if itwere commercially available, reasonably priced,and prepackaged [28]. In Japan, where onemillion cataract surgeries are performed eachyear, there was an increase in intracameralprophylaxis from\2% to approximately 12%by 2013. The use of the intracameral route inCanada has been reported to be 42.1%, and inAustralia intracameral use exceeds 80%. Intra-cameral prophylaxis is recommended by variousnational societies, including those in Italy,Turkey, Spain, Portugal, Hungary, and Finland.It is considered unethical to withhold treatmentwith the intracameral antibiotic cefuroxime inSweden unless the patient has a known cepha-losporin allergy [39].

The most common organisms associatedwith POE are Gram-positive bacteria, and thesingle most common offender is Staphylococcusepidermidis, a Gram-positive, coagulase-negativebacterium that is usually susceptible to thethree most commonly used intracameralantibiotics. A smaller, but still significant, per-centage of POE cases are due to other Gram-positive bacteria, such as Staphylococcus aureusand Streptococcus spp., Gram-negative bacteria,such as Pseudomonas aeruginosa, and, less com-monly, fungi.

The most commonly used intracameralantibiotics are cefuroxime, moxifloxacin, andvancomycin. The medical risks associated withroutine intracameral antibiotic prophylaxisinclude anaphylactic reactions, overdoses,introduction of contaminants, acquired bacte-rial resistance, and other adverse events specificto each antibiotic.

Cefuroxime is a second-generation cepha-losporin that was first introduced for systemicuse in 1987. It halts the synthesis of the pepti-doglycan layer of the bacterial cell wall, therebydisrupting cell-wall integrity. Its action is timedependent, which means it possesses bacterici-dal activity as long as the drug concentration isgreater than the minimum inhibitory

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concentration. Cefuroxime is the only one ofthese three commonly used intracameralantibiotics that has been studied in a prospec-tive, randomized, controlled trial (RCT), and ithas been discussed in the greatest number ofobservational studies. Retrospective studiesfrom Canada, France, South Africa, and Sweden,among other countries, have found significantdecreases in the rate of POE with the use ofintracameral cefuroxime. In Spain, reductionsin endophthalmitis were as high as tenfold withintracameral cefazolin, another cephalosporin[40–46] A tertiary center in Hong Kong reducedthe incidence of endophthalmitis to 0% withthe use of intracameral cefuroxime that hadbeen compounded by the hospital pharmacy[47].

During the ESCRS trial, cefuroxime wasreconstituted from powder, but a commercialpreparation (Aprokam�, Thea Pharmaceuticals,Newcastle Under Lyme, UK) is now available inEurope. However, there is no Food and DrugAdministration (FDA)-approved product avail-able for use in the USA, and the substantialbarriers to approval make it unlikely that aproduct will be approved soon [76]. The off-la-bel use of intracameral cefuroxime requires thata nurse of other professional reconstitute thedrug from a vial in the operating room or areliable compounding pharmacy must beemployed to decrease variability in dosage andprevent microbial contamination. Both strate-gies have been employed, particularly in partsof the world where cefuroxime that has beenspecifically prepared and approved for intra-cameral use is not available. Various methods ofcefuroxime preparation have been described,many of which require multiple steps, includinga two-step method to obtain a final concentra-tion of 1 mg/0.1 mL [48]. Compounding thedrug introduces a risk of infection, particularlyif the same vial of antibiotic or solvent is usedfor multiple patients.

Excessive intracameral cefuroxime maycause macular edema, anterior and posteriorsegment inflammation, retinal vascular leakageand/or infarction, uveitis, and a decrease inlong-term retinal function [49–51] Adversereactions to the standard intracameral dose of1.0 mg/0.1 mL are relatively rare and include

serous macular detachment, increased centralfoveal thickness, anterior chamber inflamma-tion, and vitritis [50]. Intracameral cefuroximeis also associated with the toxic anterior seg-ment syndrome (TASS), a vision-threatening,noninfectious inflammation that begins within24 h following surgery. TASS is characterized bycorneal endothelial dysfunction and theabsence of vitreous cells, and TASS cases oftenoccur in clusters. TASS must be differentiatedfrom infectious endophthalmitis because TASSresponds favorably to topical corticosteroidadministration and does not require antibiotics[52].

Enterococci are resistant to cefuroxime, andthe routine use of intracameral cefuroxime inSweden was associated with an increased pro-portion of Enterococci endophthalmitis cases[44]. Fungal endophthalmitis has also been seenfollowing the use of intracameral cefuroxime, asa 2009 report described seven consecutivepatients who developed Fusarium endoph-thalmitis due to a compounding error [53]. Thefinal visual outcomes for these patients werebetween light perception and 20/100 despitetreatment with local and systemic antifungalmedications. Two patients with penicillin orcephalosporin allergies suffered anaphylacticreactions following intracameral cefuroxime[54, 55], but despite these cases, cefuroxime canusually be administered safely to patients withpenicillin or cephalosporin allergies, althoughdiscussing this risk with patients may prove tobe difficult [50].

Moxifloxacin, a fourth-generation fluoro-quinolone that was first approved in 2003 fortopical ophthalmic use in the treatment ofbacterial conjunctivitis, is commonly used asintracameral prophylaxis. Moxifloxacin inhibitsDNA gyrase and topoisomerase IV, both ofwhich are necessary for bacterial cell replicationbecause they separate bacterial DNA. Of thethree commonly used antibiotics mentionedabove, moxifloxacin has the broadest spectrumof coverage, with activity against both Gram-positive and Gram-negative bacteria, includingPseudomonas aeruginosa. It is biphasic, with aninitial dose-dependent activity profile; afterinjection it remains bactericidal for a muchlonger time than cefuroxime, even at low

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injection concentrations [56]. Other advantagesof moxifloxacin for ophthalmic use include itspH, tonicity, and lack of preservative [32]. Inmost countries it must be compounded prior touse. In India, where over one million cataractsurgeries are performed each year, moxifloxacinPF hydrochloride (Promox�; Aurolab, Madurai,India) for intracameral use has been manufac-tured since 2013, and it currently accounts formore than 90% of intracameral antibiotic use inIndia [58]. The Aravind Eye Care System, whichcomprises ten surgical facilities and considersintracameral moxifloxacin to be standard-of-care after routine surgery, demonstrated afourfold reduction in the rate of endoph-thalmitis following cataract surgery [57].Unfortunately, moxifloxacin may be becomingless effective as a prophylaxis for endoph-thalmitis because repeated contact with ocularand nasopharyngeal flora has promoted thegrowth of resistant bacteria [59]. Coagulase-negative Staphylococcus spp. have becomeincreasingly resistant to all fluoroquinolones,including moxifloxacin, with susceptibilityrates that have decreased from 77.0% to 43.0%since 2004 [60]. Moxifloxacin is the mostexpensive of the three current antibiotics ofchoice, and routine use would significantlyincrease the total cost of cataract surgery in theUSA. The use of intracameral moxifloxacin isnot supported by level I evidence.

Vancomycin inhibits cell-wall synthesis in atime-dependent manner similar to cefuroxime.It is effective against nearly all Streptococci andStaphylococci species, including methicillin-re-sistant Staphylococcus aureus (MRSA), which maycause up to 2% of POE. It has no activity againstthe majority of Gram-negative organisms,which have been reported to cause up to 10% ofPOE [61]. Vancomycin was approved by theFDA in 1958 for intravenous administration,and although there is no commerciallyapproved intraocular formulation, it is a com-monly used intravitreal antibiotic for the treat-ment of endophthalmitis. When usedprophylactically, 1 mg/0.1 mL is injected at thecompletion of cataract surgery. A large (14,805cataract cases) retrospective cohort study fromAustralia demonstrated a ninefold reduction inendophthalmitis (0.43% vs. 0.049%; P

\0.0001) during the years 2000–2014 follow-ing the introduction of vancomycin prophy-laxis [62]. Vancomycin has become theantibiotic of choice for 12.1% of Australianophthalmologists who routinely use intracam-eral antibiotics [63]. A meta-analysis thatincluded 17 studies found a lower averageweighted incidence of POE with vancomycincompared to cefuroxime and moxifloxacin(0.0106%, 0.0332%, and 0.0153%, respectively)[61].

The routine use of vancomycin is of consid-erable concern because it has been associatedwith hemorrhagic occlusive retinal vasculitis(HORV), which is a delayed-onset/type IIIhypersensitivity reaction. HORV was firstreported in 2014, and the first case from Aus-tralia, where vancomycin seems to be mostpopular, was reported in 2016. In light of van-comycin’s known systemic effects, it has beensuggested that HORV represents a leukocyto-clastic retinal vasculitis. However, recenthistopathologic examination of an enucleatedeye suggests that HORV may be a primarychoroidopathy, with secondary effects on theoverlying retina [64, 65]. All cases of HORVpresent within 2 weeks of surgery, usually withpainless vision loss and minimal vitreousinflammation. A 2016 joint task force of theAmerican Society of Retina Specialists and theASCRS reported that patients seek treatment forHORV at an average of 8 days after cataractsurgery. Visual acuity results from HORV arepoor, with 61% of eyes (22/36) having 20/200 orworse and 22% (8/36) losing all perception oflight [66]. Prophylactic use of vancomycinpotentially compromises its efficacy as a treat-ment for POE because it may promote thedevelopment of resistant organisms. A 2016literature review noted poor visual outcomes in27 cases of endophthalmitis due to organismswith either reduced susceptibility or resistanceto vancomycin [67]. Additionally, vancomycinis not active against Gram-negative organisms,which are responsible for a small percentage ofPOE cases.

The economic risks of routine intracameralprophylaxis ought to be noted, since a pro-hibitively high cost is the primary reason givenby Americans for not accessing health care [68].

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Routine use of intracameral antibiotics maysignificantly increase healthcare costs. Approx-imately three million cataract surgeries are per-formed each year in the USA. The acquisitionand patient costs of the three commonly usedantibiotics are as follows: cefuroxime ($5.08 and$80.16); vancomycin ($82.08 and $234.16); andmoxifloxacin ($41.18 and $152.36). Someoperating rooms obtain multiple doses ofantibiotics from a single vial, a practice that iscontrary to the recommendations in chap-ter 797 of the United States Pharmacopoeia(United States Pharmacopeial Convention,Rockville, MD, USA) and should be avoided ifpossible. Pharmacokinetic studies show thathalf of the injected cefuroxime is eliminatedfrom the anterior chamber approximately 4–5 hafter surgery, yet organisms may enter a non-sutured anterior chamber from the eyelids andthe environment at any time during the firstfew postoperative days. This phenomenon callsinto further question the efficacy and financialpracticality of routine intracameral antibioticuse [69].

POST-OPERATIVE CARE

Many patients are treated with topical antibi-otics post-operatively despite the fact that nodrops have been approved by the FDA for rou-tine use with cataract surgery. A 2017 reviewarticle noted that most ophthalmologiststhroughout the world prescribe topical antibi-otics post-operatively, although the results fromRussia and Mexico included in this review arti-cle were based on unpublished data [70]. Thereis no uniformly preferred regimen, so the choiceof antibiotics depends on the surgeon’s prefer-ence, with the most common choices beingsimilar to those prescribed pre-operatively,including fluoroquinolones, aminoglycosides,and chloramphenicol. Additionally, trimetho-prim-polymyxin B and tobramycin provideexcellent coverage against Staphylococcus spp.,with 87.5% and 93.6% of colonies being sensi-tive to each of the respective antibiotics.Trimethoprim-polymyxin B has the addedbenefit of covering Streptococcus pneumoniae andPseudomonas [71]. The best time to start

antibiotics in the post-operative patient has notbeen determined, and timing thus variesaccording to surgeon preference. In the ESCRSstudy, topical antibiotics were started the dayfollowing surgery rather than immediately post-operatively. A retrospective study from theMoran Eye Center demonstrated an increasedrisk of endophthalmitis when antibiotics werestarted the day after surgery rather than on theday of surgery (odds ratio 13.7; P = 0.05) [72].

Subconjunctival injections of antibiotics andsteroids are commonly administered after manyintraocular procedures, but their use followingcataract surgery is decreasing. For cataractsurgeries, however, the major beneficiaries ofsubconjunctival injections are patients who, forany variety of reasons, may be unable to complywith a post-operative eye drop regimen. Choicesof antibiotics include cefuroxime and gentam-icin, in addition to corticosteroids, such asmethylprednisolone. Despite concerns regard-ing penicillin hypersensitivity, a study by Mittraand McElvanney of 36 patients with penicillinallergy who had previous reactions rangingfrom rashes to loss of consciousness foundcross-reaction with subconjunctival cefuroximeinjections to be low [73]. These authors alsoconcluded that cefuroxime is better than manyother drugs because of its broad spectrum bac-tericidal activity and low toxicity [73]. Subcon-junctival injections of methylprednisolone maybe as safe and effective as drops, with the addedbenefit of nullifying compliance issues [74].

MAYO CLINIC DATA

The ESCRS trial is frequently cited for providingthe best evidence in support of the prophylacticintracameral use of antibiotics. This multicen-ter, prospective, multi-armed trial studied13,698 patients at 24 ophthalmology centersthroughout Europe. Patients were randomizedto one of four groups: no prophylactic antibi-otics; topical antibiotics only; intracameralcefuroxime only; both topical antibiotics andintracameral cefuroxime. Cefuroxime wascompounded for intracameral use because asingle-use commercial product was not yetavailable. The primary endpoint was the

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development of endophthalmitis. The inci-dences of endophthalmitis among the fourgroups were 13/3438 (0.38%), 10/3424 (0.29%),3/3408 (0.09%), and 2/3428 (0.06%), respec-tively. As detailed in Table 1, the incidence ofendophthalmitis was significantly better inpatients who received intracameral cefuroxime(5/6836; 0.07%) than in those who did notreceive cefuroxime (23/6862; 0.33%), but theincidence of endophthalmitis in patients whoreceived levofloxacin eye drops (12/6852;0.18%) was not significantly different fromthose who did not receive drops (16/6846;0.23%). The following risk factors for thedevelopment of endophthalmitis were alsonoted: clear corneal incision (5.889 higher)versus scleral tunnel incision; silicone intraoc-ular lens (3.39 higher) versus acrylic lens; andsurgical complications (4.959 higher) versusnone.

Several problems with the design and resultsof the ESCRS trial deserve discussion. Thecefuroxime required compounding at each sitebecause the commercially available product,now used throughout Europe, was not availableat the time of the trial. The levofloxacin eyedrops were started the day after surgery. Thetrial was stopped prematurely because of anapparent treatment effect in favor of intracam-eral cefuroxime.

One of the major problems with the ESCRStrial was the very high rate of endophthalmitis(0.33%) in the cohorts not receiving intracam-eral cefuroxime. This surprisingly high ratemore easily allowed intracameral cefuroxime tosignificantly improve the endophthalmitis rateover cohorts not receiving cefuroxime. Webelieve that good aseptic technique by theoperating room staff (equipment sterilization,operating theater construction, room setup,gowns, gloves and other factors) combined withgood surgical technique should produceendophthalmitis rates that not only exceedthose of the non-intracameral antibioticcohorts in the ESCRS trial, but should also rivalthe rates achieved with the injection ofcefuroxime.

To test the above hypothesis, we determinedthe post-cataract extraction endophthalmitisrates from the three major ophthalmology sites

within the Mayo Clinic Foundation—Arizona,Minnesota, and Florida. The sites functionindependently, with little exchange of staffbetween operating rooms and Ophthalmologydepartments, but aseptic and surgical proce-dures and techniques are frequently discussedby all sites and, when possible, converged.

Senior cataract surgeons at each of the threesites were asked to provide a retrospective totalof cataract surgeries and endophthalmitis casesfor the 5-year period 2012–2016. During thisperiod, topical fluoroquinolone antibiotic dropswere used routinely before and after surgery, butintracameral antibiotics were not used. Asdetailed in Table 2, the numbers of endoph-thalmitis cases, cataract surgeries, and endoph-thalmitis rates were as follows: Arizona—1/3535, 0.028%; Florida—1/4495, 0.022%; Min-nesota—3/16250, 0.0185%. The aggregate ratewas 0.02%. This compares favorably with theESCRS endophthalmitis rate in eyes thatreceived intracameral cefuroxime—0.073%.A Chi-square analysis determined that the MayoClinic endophthalmitis rate without the use ofintracameral antibiotics was significantly betterthan the ESCRS rate with intracameralcefuroxime (P = 0.03).

DISCUSSION

Post-operative endophthalmitis is not a ‘‘neverevent,’’ but with careful attention to detail,endophthalmitis rates from most ophthalmo-logic surgical facilities can probably beimproved. Strict antisepsis practices should bethe primary approach to endophthalmitis pre-vention since they are supported by centuries ofsurgical practice and will likely have the greatestand longest lasting impact. Surgeons wishing toimprove their endophthalmitis rates shouldcarefully assess all aspects of their operatingroom preparation and sterile technique. The useof povidone-iodine is the only antibiotic/an-tisepsis practice supported by level I evidence,but despite this, use of povidone-iodine is only94% in India, and some aspects of preparationmay not be fully optimized [58]. The authorsbelieve that unless endophthalmitis rateswithin an institution are less than 1/1000

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(0.1%), surgeons should critically evaluate theirasepsis practices. Intracameral antibiotics can beincorporated into their practices, but unlessasepsis is carefully and systematically opti-mized, endophthalmitis rates will always behigher than is necessary.

Among U.S. cataract surgeons, 47% eitheruse or plan to use routine intracameral antibi-otics, and it has been estimated that between30% and 50% of all antibiotic use in ambulatorymedicine is unnecessary or inappropriate[75, 76]. Inappropriate use of antibiotics addssignificantly to the cost of medical care, exposespatients to unnecessary risks of drug-relatedadverse events, and increases the prevalence ofantibiotic-resistant organisms. Before adoptingthe routine use of intracameral antibiotics,ophthalmologists need to consider the largeburden of unnecessary treatment that is associ-ated with intracameral prophylaxis.

Gower et al. found high-certainty evidencethat intracameral cefuroxime with or withouttopical levofloxacin lowers the risk of endoph-thalmitis, and moderate evidence that the two

methods together are better than either alone[33]. However, the heterogeneity of the studydesigns and modes of antibiotic delivery amongreported studies made it impossible for them toconduct a formal meta-analysis [33]. A recentmeta-analysis of 33 studies identified con-founding variables and protocol deviations asthe principle causes of moderate to high bias,and lack of homogeneity between studies wascited as the greatest challenge to comparingstudies [61].

There is no FDA-approved product availablefor intracameral use in the USA at this time andpreparing the antibiotics requires a reliablecompounding pharmacy or a skilled nurse inthe operating theater. While cefuroxime may beeffective, it is not without risks. Javitt arguesthat the economic return on making anapproved product readily available to U.S.physicians is likely to be minimal [77].

In light of the available data, routine use ofintracameral antibiotics should be carefullyconsidered since the ESCRS study remains theonly RCT published to date. Results from recent

Table 1 European Society of Cataract and Refractive Surgery trial rates of endophthalmitis

Cohort Number of surgeries Cases of endophthalmitis Rate of endophthalmitis (%)

No ICC 6862 23 0.335

ICC arm 6836 5 0.073

Aggregate 13,698 28 0.204

ICC Intracameral cefuroximeThis table lists the endophthalmitis rates from the European Society of Cataract and Refractive Surgery EndophthalmitisStudy (ESCRS) in eyes that did and did not receive intracameral cefuroxime

Table 2 Mayo Clinic foundation rates of endophthalmitis

Site Number of surgeries Cases of endophthalmitis Rate of endophthalmitis (%)

Arizona 3535 1 0.028

Florida 4495 1 0.022

Minnesota 16,250 3 0.019

Aggregate 24,245 5 0.021

This table lists the 5-year post-cataract surgery endophthalmitis rates from the three major Mayo Clinic DestinationMedical Centers

Ophthalmol Ther (2018) 7:233–245 241

‘‘big data’’ reports and large retrospective studiesare compelling, but these studies have limita-tions in study design and potential inaccuraciesin diagnosis and procedure coding. Nonethe-less, the strong trend throughout much of theworld favors increasing the routine use ofintracameral antibiotics. Surgeons electing toroutinely use intracameral antibiotics shouldoptimize their aseptic practices, adequatelytrain staff in the preparation and use of antibi-otics, and vigilantly monitor patients forantibiotic-related complications. Finally, inorder to provide surgeons with reliable, action-able data, a carefully designed, multicenter RCTevaluating the efficacy of intraocular antibioticsneeds to be performed.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thismanuscript, take responsibility for the integrityof the work as a whole, and have given finalapproval for the version to be published.

Disclosures. Nicholas K. George has nothingto disclose. Michael W. Stewart, Alkahest:Consultant, Allergan: Institutional researchsupport, Bayer: Consultant, Regeneron: Institu-tional research support

Compliance With Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in any

medium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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