postcataract surgery endophthalmitis is a relatively uncommon but devastating complication of modern cataract surgery , and there is not complete consensus regarding the ideal practice patterns for prophylaxis .
the european society of cataract and refractive surgeons ( escrs ) prospective multi - center interventional trial ( and many other case  control , cross - sectional , and longitudinal studies ) supported the hypothesis that the use of icc at the conclusion of cataract surgery reduces the incidence of postoperative endophthalmitis .
it is estimated that two to four cases of endophthalmitis per 1000 surgeries can be avoided if surgeons adopt the use of icc , and the absence of an icc prophylactic regimen at a dose of 1 mg/0.1 ml was associated with an almost 5-fold increase in the risk of postoperative endophthalmitis . the injection is expedient , painless , and achieves high antibiotic concentrations in the immediate postoperative period . in addition , intracameral injection may be particularly effective in patients who sustain posterior capsule rupture and would otherwise incur an increased the risk of endophthalmitis . when considering the implementation of any intervention , cost - effectiveness is another important variable .
estimated the cost - effectiveness ratio for icc to be $ 1403 per case of postoperative endophthalmitis prevented .
many commonly used topical antibiotics are not cost - effective compared with icc , even under optimistic assumptions about their efficacy .
another economic analysis comparing different prophylaxis regimens concluded that icc provided the best cost - effectiveness ratio .
therefore , the decision to adopt this therapy is supported by studies demonstrating efficacy and cost - effectiveness . the final variable that must be included when
one weakness inherent in any meticulously performed clinical trial is that the results may not be generalizable to a more diverse patient population and varying scenarios of care .
most clinical trials make great effort to reduce the risk of enrollment in the study , and therefore the safety profile reported may be a  best - case scenario . 
the purpose of this review is to provide an evidence - based review and synthesis of the literature regarding the risks of icc when administered for the prevention of postcataract surgery endophthalmitis , thereby informing decisions regarding best practices for cataract surgery .
the categories of risk to be reviewed are : 
 risk of anaphylaxis , especially in penicillin or cephalosporin allergic patientsrisk of toxicity at routine clinical dosesrisk of toxicity at increased doses due to compounding errorsidiosyncratic reactions , including toxic anterior segment syndrome ( tass ) . 
 
risk of anaphylaxis , especially in penicillin or cephalosporin allergic patients risk of toxicity at routine clinical doses risk of toxicity at increased doses due to compounding errors idiosyncratic reactions , including toxic anterior segment syndrome ( tass ) .
we performed a systematic review of the existing scientific literature using pubmed and google scholar .
the key words used were  cefuroxime ,   endophthalmitis  and  cataract surgeries .
all articles were read in full by both authors with the exception of two that were available only as abstracts .
the highest level of evidence for each aspect of the intervention was assigned utilizing the oxford center for evidence - based medicine guidelines .
cross - reactivity between penicillins and most second- and all third- and fourth - generation cephalosporins is negligible .
it is generally considered safe to administer a cephalosporin with a side chain that is structurally dissimilar to that of penicillin . in patients with a documented ige - mediated reaction to penicillin , use of cephalosporins with a similar side chain
however , cephalosporins with different side chains ( such as cefuroxime ) may be given .
it should be noted that the escrs study excluded patients with penicillin or cephalosporin allergy , as did several other large studies .
icc injection during cataract surgery was well tolerated in a prospective study of forty penicillin - allergic patients with a negative preoperative cefuroxime skin test .
the use of icc in patients with penicillin allergy was explored between 2004 and 2012 in a case  control registry study ; the control group was the cohort of patients undergoing cataract surgery under a hospital policy of excluding patients with self - reported penicillin allergy .
after a critical review of the literature and pilot study in 817 patients with reported penicillin allergy , this policy was altered , and all patients without a specific history of cephalosporin anaphylactic reaction were administered icc . out of 13,592 subsequent cataract surgeries , there were no reported cases of anaphylaxis or allergic reaction .
this study is limited by the registry design , which may underreport or miscategorize adverse events .
a similar longitudinal observational study by shorstein et al . reported a decreasing endophthalmitis rate after instituting a standard icc protocol ; there were no reports of anaphylaxis or allergic reaction among 12,609 surgeries , but some patients received other intracameral antibiotics , and it is unclear if penicillin - allergic patients routinely received cefuroxime or other antibiotics such as moxifloxacin or vancomycin .
control study comparing the endophthalmitis rates before and after instituting a standard icc regimen ; patients with cefuroxime allergy were excluded , but penicillin - allergic patients received icc .
there were no cases of anaphylaxis among 2289 patients receiving icc , but the prevalence of penicillin allergy was not reported .
there are two case reports of an anaphylactic reaction in penicillin or cephalosporin allergic patients who received icc .
the number of patients from these centers that had received icc were not reported , preventing an estimation of the incidence of this complication .
adverse effects that have rarely been reported with routine clinical doses include serous macular detachment , cystoid macular edema ( cme ) , increased central foveal thickness , decreased best - corrected distance visual acuity , anterior chamber inflammation , and vitritis .
however , a prospective study found that icc at the standard dose of 1 mg/0.1 ml did not have a statistically significant effect on postoperative macular thickness compared with nonadministration of intracameral antibiotic ; although , this study was under - powered to detect rare events .
the escrs study and other longitudinal cohort studies were not designed to assess safety or adverse events as primary endpoints , but a large number of patients enrolled without a reported increase in these adverse events suggests that they are not associated , are masked by confounding factors , or are exceedingly rare .
a lingering concern for some ophthalmologists is the risk of ocular toxicity attributable to inadvertent exposure to elevated concentrations ( typically due to compounding errors ) .
high doses of cefuroxime are associated with anterior and posterior segment inflammation with fibrin formation , corneal edema , elevated intraocular pressure , serous macular detachment , cme , hemorrhagic retinal infarction , and reduced rod photoreceptor cell function by electroretinography .
table 1 summarizes the reported complications related to inadvertent administration of increased concentrations or volumes of cefuroxime .
a limitation in assigning risk based on studies such as this is the lack of incidence data ; it is unknown how many patients have received increased doses of icc , and therefore , the rate of these adverse events is unknown .
the incidence rate of compounding errors for icc is also unknown and is presumably highly dependent on local factors such as the mechanisms of medication preparation and quality control measures .
adverse events attributed to cefuroxime compounding errors tass after cataract surgery has been reported in association with the intracameral use of cefuroxime .
reported an ongoing cluster of tass cases at a single center , with a resolution of the outbreak after discontinuing icc in favor of intracameral moxifloxacin .
as expected , there was no  rechallenge  in affected patients to determine conclusively if cefuroxime or other factor contributed to tass .
there was also no reported analysis of cefuroxime concentration to ascertain the potential role of dilution errors or other factors related to preparation .
no other studies were found that studied the relationship of cefuroxime to tass , or the effects of specific interventions to reduce the incidence of tass related to cefuroxime .
cross - reactivity between penicillins and most second- and all third- and fourth - generation cephalosporins is negligible .
it is generally considered safe to administer a cephalosporin with a side chain that is structurally dissimilar to that of penicillin . in patients with a documented ige - mediated reaction to penicillin , use of cephalosporins with a similar side chain
however , cephalosporins with different side chains ( such as cefuroxime ) may be given .
it should be noted that the escrs study excluded patients with penicillin or cephalosporin allergy , as did several other large studies .
icc injection during cataract surgery was well tolerated in a prospective study of forty penicillin - allergic patients with a negative preoperative cefuroxime skin test .
the use of icc in patients with penicillin allergy was explored between 2004 and 2012 in a case  control registry study ; the control group was the cohort of patients undergoing cataract surgery under a hospital policy of excluding patients with self - reported penicillin allergy .
after a critical review of the literature and pilot study in 817 patients with reported penicillin allergy , this policy was altered , and all patients without a specific history of cephalosporin anaphylactic reaction were administered icc . out of 13,592 subsequent cataract surgeries , there were no reported cases of anaphylaxis or allergic reaction .
this study is limited by the registry design , which may underreport or miscategorize adverse events .
a similar longitudinal observational study by shorstein et al . reported a decreasing endophthalmitis rate after instituting a standard icc protocol ; there were no reports of anaphylaxis or allergic reaction among 12,609 surgeries , but some patients received other intracameral antibiotics , and it is unclear if penicillin - allergic patients routinely received cefuroxime or other antibiotics such as moxifloxacin or vancomycin .
control study comparing the endophthalmitis rates before and after instituting a standard icc regimen ; patients with cefuroxime allergy were excluded , but penicillin - allergic patients received icc .
there were no cases of anaphylaxis among 2289 patients receiving icc , but the prevalence of penicillin allergy was not reported .
there are two case reports of an anaphylactic reaction in penicillin or cephalosporin allergic patients who received icc .
the number of patients from these centers that had received icc were not reported , preventing an estimation of the incidence of this complication .
adverse effects that have rarely been reported with routine clinical doses include serous macular detachment , cystoid macular edema ( cme ) , increased central foveal thickness , decreased best - corrected distance visual acuity , anterior chamber inflammation , and vitritis .
however , a prospective study found that icc at the standard dose of 1 mg/0.1 ml did not have a statistically significant effect on postoperative macular thickness compared with nonadministration of intracameral antibiotic ; although , this study was under - powered to detect rare events .
the escrs study and other longitudinal cohort studies were not designed to assess safety or adverse events as primary endpoints , but a large number of patients enrolled without a reported increase in these adverse events suggests that they are not associated , are masked by confounding factors , or are exceedingly rare .
a lingering concern for some ophthalmologists is the risk of ocular toxicity attributable to inadvertent exposure to elevated concentrations ( typically due to compounding errors ) .
high doses of cefuroxime are associated with anterior and posterior segment inflammation with fibrin formation , corneal edema , elevated intraocular pressure , serous macular detachment , cme , hemorrhagic retinal infarction , and reduced rod photoreceptor cell function by electroretinography .
table 1 summarizes the reported complications related to inadvertent administration of increased concentrations or volumes of cefuroxime . a limitation in assigning risk based on studies such as this is the lack of incidence data ; it is unknown how many patients have received increased doses of icc , and therefore , the rate of these adverse events is unknown .
the incidence rate of compounding errors for icc is also unknown and is presumably highly dependent on local factors such as the mechanisms of medication preparation and quality control measures .
tass after cataract surgery has been reported in association with the intracameral use of cefuroxime .
reported an ongoing cluster of tass cases at a single center , with a resolution of the outbreak after discontinuing icc in favor of intracameral moxifloxacin .
as expected , there was no  rechallenge  in affected patients to determine conclusively if cefuroxime or other factor contributed to tass .
there was also no reported analysis of cefuroxime concentration to ascertain the potential role of dilution errors or other factors related to preparation .
no other studies were found that studied the relationship of cefuroxime to tass , or the effects of specific interventions to reduce the incidence of tass related to cefuroxime .
the efficacy of icc as a prophylaxis for postcataract surgery endophthalmitis has been well established , but concerns regarding the risks of this intervention remain .
the consensus of the literature from systemic administration of antibiotics is that the risk of cross - reactivity between second - generation cephalosporins ( such as cefuroxime ) and penicillin is very low .
our review of the literature supports a low rate of anaphylactic reactions , even among penicillin - allergic patients . a postal survey conducted among consultant ophthalmic surgeons working in the national health service ophthalmic departments in england revealed that of 262 consultants , 103 ( 37% ) used cefuroxime in patients allergic to penicillin .
we propose that an acceptable practice pattern would be to consider icc in all cataract surgery patients , including those with a history of penicillin allergy ; administration to those patients with cephalosporin allergy may be considered , but skin testing may be indicated to identify those patients that are at increased risk of anaphylaxis and should not receive icc .
alternative intracameral antibiotics , such as vancomycin and moxifloxacin , may reduce the risk of anaphylaxis in cefuroxime - allergic patients , but the efficacy of those interventions has been less well established .
the latest survey of members of the american society of cataract and refractive surgeons revealed that 30% of the united states ophthalmologists were utilizing intracameral antibiotics , compared to 70% of european respondents .
however , many us cataract surgeons believe that intra - cameral antibiotics are unnecessary , based on concerns about the methodology of the escrs and other studies , or that the absolute benefits do not outweigh the risks of dilution errors and toxicity . not surprisingly , a clinical study demonstrated that the mathematical accuracy of a dilution protocol does not ensure dosage accuracy in a real - world clinical scenario .
the authors suggest that a commercial preparation would likely reduce the risk of dilution errors , but commercial preparations of intracameral antibiotic agents may not be financially viable in all health care environments .
implementation of icc should include measures to audit and provide quality assurance of the cefuroxime dilution protocol .
half of the risk - benefit equation of icc has been solved to the satisfaction of most clinicians ; the efficacy is clear .
the remaining barriers to more widespread adoption include concerns about risks such as anaphylaxis , dilution errors , and toxicity ( especially with noncommercial preparation ) and finally , the additional costs of this therapy .
since endophthalmitis is a rare event , even a slight increase in the risk of prophylactic therapy may negate the potential benefits .
our review and synthesis of the literature regarding the risks of cefuroxime therapy support the following recommendations : 
 cefuroxime may be used safely in patients with penicillin allergy ( level 2a evidence)efforts to reduce the risk of dilution errors may include the use of a commercially prepared product , or strict quality assurance measures ( level 4 evidence)routine measures to reduce tass should also apply to the use of cefuroxime ( level 5 evidence ) ; even though , there is no proven association . 
 
cefuroxime may be used safely in patients with penicillin allergy ( level 2a evidence ) efforts to reduce the risk of dilution errors may include the use of a commercially prepared product , or strict quality assurance measures ( level 4 evidence ) routine measures to reduce tass should also apply to the use of cefuroxime ( level 5 evidence ) ; even though , there is no proven association .
future studies may further define the cost - effectiveness of icc , and continued efforts to reduce the risk attributable to dilution errors are indicated .
finally , comparative studies of the efficacy and safety of cefuroxime compared to other intracameral antibiotics are needed to help define the optimal endophthalmitis prophylaxis regimen for our patients undergoing cataract surgery .
 background : endophthalmitis after cataract surgery is a rare but vision - threatening complication . 
 intracameral cefuroxime ( icc ) has been reported to be effective at reducing the risk , but concerns regarding the risks associated with this intervention remain.methods:systematic review and synthesis of the literature on icc , with a focus on the risks of therapy.results:level 2a evidence was found to support the use of cefuroxime in penicillin - allergic patients . compounding or dilutional errors are associated with ocular toxicity , but the incidence and risk of this occurrence are unknown . 
 level 4 evidence supports interventions that reduce the risk of dilutional errors . 
 the association of cefuroxime injection with toxic anterior segment syndrome ( tass ) is not established ; level 5 evidence supports standard measures to reduce the incidence of tass related to cefuroxime administration.conclusion:cefuroxime can be administered safely to penicillin - allergic patients , and steps should be taken to reduce the risk of compounding or dilutional errors to avoid negating the benefits of this intervention . 
 recommended practice patterns for endophthalmitis prophylaxis should consider the risks and benefits of icc . 