Expert Review of Ophthalmology

ISSN: 1746-9899 (Print) 1746-9902 (Online) Journal homepage: https://www.tandfonline.com/loi/ierl20

Postoperative endophthalmitis after cataract

surgery: A worldwide review of etiology, incidence
and the most studied prophylaxis measures

Andrzej Grzybowski, Jagger C. Koerner & Mary J. George

To cite this article: Andrzej Grzybowski, Jagger C. Koerner & Mary J. George (2019):
Postoperative endophthalmitis after cataract surgery: A worldwide review of etiology,
incidence and the most studied prophylaxis measures, Expert Review of Ophthalmology, DOI:
10.1080/17469899.2019.1674140

To link to this article: https://doi.org/10.1080/17469899.2019.1674140

Accepted author version posted online: 28

Sep 2019.

Submit your article to this journal

Article views: 3

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ierl20
 Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Expert Review of Ophthalmology

DOI: 10.1080/17469899.2019.1674140
Review

Postoperative endophthalmitis after cataract surgery: a worldwide review of etiology, incidence and

t
the most studied prophylaxis measures

ip
Andrzej Grzybowski1*; Jagger C. Koerner2; Mary J. George3
1
Department of Ophthalmology, Univeristy of Warmia and Mazury, Olsztyn, Poland

cr
2
Wake Forest University, Department of Ophthalmology, Winston Salem, North Carolina, USA
3
Albany Medical College, Department of Microbiology, Albany, New York

us
*Corresponding author: Andrzej grzybowski, Institute for Research in Ophthalmology, Foundation for
Ophthalmology Development, 60-554 Gorczyczewskiego 2/3, Poznan, email: ae.grzybowski@gmail.com
an
M
ed
pt
ce
Ac

Information Classification: General

 Abstract
Introduction: Endophthalmitis is a significant and potentially severe complication of cataract surgery.
Cataract surgeons have several intraoperative prophylactic maneuvers to choose from to prevent this

t
rare but serious complication.

ip
Areas covered: The epidemiology, etiology, and practice patterns regarding endophthalmitis prophylaxis
are discussed; including a detailed review of the medications used intracamerally and use of povidone
iodine. Articles were identified by PubMed literature search of published English-language articles.

cr
Literature in PubMed before June 2019 was reviewed without a date limit in the past. The terms
“intracameral antibiotic,” “povidone-iodine,” “moxifloxacin,” “vancomycin,” “cefuroxime,”
“prophylaxis”, and “incidence” were combined with the terms “prevention,” “endophthalmitis,” and

us
“antisepsis protocol.” The reference lists of relevant articles were reviewed to identify additional
articles, and this process was iterated several times.
Expert opinion: The use of intracameral antibiotic prophylaxis (ICAP), after considering availability, cost
an
and the postoperative endophthalmitis rate (POER) without ICAP, should be considered. Povidone
iodine (PI) was shown to be an effective prophylactic measure against POE. Frequent topical application
of dilute PI solution during surgery has an excellent safety profile, and significantly reduces the anterior
chamber contamination rate after cataract surgery. Although further studies of dilute PI in cataract
M
surgery are needed, its use could massively reduce antibiotic use, cost and the risk of promoting
bacterial resistance.

Article highlights
ed

• ICAP can decrease POER; after considering availability, cost and the POER without ICAP,
its use should be considered.
• This effect of ICAP, however, was shown particularly in high POER; there is no evidence
that ICAP can decrease POER lower than 0.02%.
pt

• Intraoperative complications, esp. PCR with vitreous loss increase the POER significantly,
thus the use of ICAP seems to be reasonable in these situations.
• There is some evidence that with ICAP topical antibiotics are not needed, this should be
ce

further studied and if appropriate a recommendation to avoid topical antibiotics with

ICAP included in official practice guidelines.
• Dilute PI solution has an excellent safety profile, and significantly reduces the anterior
chamber contamination rate after cataract surgery.
Ac

• Further study of dilute PI in cataract surgery is needed, if an antiseptic could achieve

POER rates similar to ICAP it could reduce antibiotic use, cost and the risk of promoting
bacterial resistance

Information Classification: General

 1. Introduction
Endophthalmitis is a significant complication of cataract surgery, limiting the visual potential of the eye.
In severe cases it can even lead to blindness. While improvements of surgical technology, techniques

t
and procedures have improved cataract surgery considerably, the widespread adoption of unsutured

ip
clear corneal incisions has created an additional risk factor for endophthalmitis. There are several
intraoperative prophylactic measures for surgeons to choose from. Therefore, awareness about
etiology, epidemiology, risk factors and prevention measures is necessary for ophthalmic surgeons.

cr
2. Epidemiology
The incidence of post-cataract endophthalmitis varies among several countries from 0.03% to 0.7%. [1-

us
13] The recommendations of the European Registry of Quality Outcomes for Cataract and Refractive
Surgery (EUREQUO), have set the maximum acceptable level of postoperative endophthalmitis (POE)
after cataract extractions at 0.05%. [14]
an
Surgical complications (wound leak, posterior capsule rupture, vitreous loss or zonular
complications) are related with higher incidence of postoperative endophthalmitis. Elderly patients (>85
years), those with clear corneal incisions versus scleral tunnel incisions, and those without intracameral
injection of cefuroxime have also a higher risk of infection. Several studies from different regions found
M
an increased relative risk of endophthalmitis with clear corneal incisions compared to scleral tunnel or
limbal incisions (RR approximately 2.0-3.0). Endophthalmitis occurs infrequently (0.05-0.08%) using
scleral tunnel or limbal incisions. The widespread adoption of clear corneal incisions, therefore, caused
an increase in POE, and consequently the magnitude of the effect of prophylactic measures such as
ed

intracameral antibiotics is related to this.[15, 16] The type of IOL is also considered as a risk factor.
Patients with silicone IOLs have higher probability of endophthalmitis compared to those with acrylic (or
other material) IOLs. According to Aaberg, the highest incidence of endophthalmitis was observed after
secondary IOL implantation and the lowest after pars plana vitrectomy (PPV). [17] However, most
pt

postoperative endophthalmitis develops after cataract surgery. [18]

3. Etiology
ce

Endophthalmitis is a serious inflammation due to an infectious process from bacteria, fungi, or parasites
that enter the eye during perioperative period. It may be divided into several categories, by the cause of
the infection, the onset of symptoms, or the degree of inflammation. Most cases of endophthalmitis are
exogenous, and occur after eye surgery (postoperative endophthalmitis), after penetrating ocular
Ac

trauma (post-traumatic endophthalmitis), or as an extension of keratitis. Most postoperative

endophthalmitis develops after cataract surgery, as an acute-onset or delayed-onset postoperative
endophthalmitis, however it can be also a complication of glaucoma surgery (associated with either
conjunctival filtering bleb, or glaucoma drainage devices) or intravitreal injections. Endogenous
endophthalmitis is an uncommon condition that can arise from bacteremic or fungemic seeding of the
eye via the bloodstream. The most common pathogens in endophthalmitis vary by category. Acute-
onset post-cataract endophthalmitis is most frequently caused by coagulase-negative staphylococci, and
chronic post-cataract endophthalmitis by Propionibacterium acnes. Regardless of category, the most
important component of treatment is the intravitreal injection of antibiotics, along with vitrectomy in
some cases. Common sources of infection in post-cataract endophthalmitis are microorganisms derived

Information Classification: General

 from the conjunctival sac, contaminated devices, irrigating solutions, the implanted intraocular lens, or
airborne contamination. According to the Endophthalmitis Vitrectomy Study, the intraocular isolates in
most cases of patients with bacterial endophthalmitis were indistinguishable from conjunctival and lid
specimens. [19] However, the microbial spectrum of postoperative endophthalmitis is dependent on
environmental, geographical or climatic factors and varies significantly in different countries. [7, 11, 20-
26]
Table 1 [27] presents the etiology of post-cataract endophthalmitis in different regions of the world.
In Europe, the most commonly isolated organisms are Gram-positive bacteria, including Staphylococcus
epidermidis, Staphylococcus aureus and Streptococcus pneumoniae, while Gram-negative bacteria are

t
in the minority. However, there are significant differences in a rate of enterococcal infections in Sweden

ip
(30-31%) compared with other European countries (2% in Netherlands and UK), or the USA (3%). [5, 7,
11] This may be connected with extensive use of intracameral cefuroxime in Sweden and increased
proportion of cefuroxime resistant species. In the USA, as in Europe the rate of streptococcal infections

cr
is lower, whereas Coagulase-Negative Staphylococci (CNS) are the most commonly identified
microorganisms. In tropical regions of Asia, the reported percentage of Gram-negative and fungal cases
is much higher than in Europe and the USA. [23-26] It should be emphasized that the main prognostic

us
factor predictive of the final visual result in patients with post-cataract endophthalmitis is bacterial
virulence level. Streptococcal strains are often virulent, producing exotoxins, thus associated with poor
visual outcome.
an
4. Different practice patterns worldwide.
Prophylaxis patterns against infectious postoperative endophthalmitis differ worldwide. In 2007 the
European Society of Cataract and Refractive Surgeons (ESCRS) published the largest study on
M
perioperative prophylaxis of postoperative endophthalmitis. It was randomized and controlled multi-
center study conducted in twenty-four ophthalmology units and eye clinics in nine European countries.
The study showed that intracameral injection of cefuroxime reduced five-fold the risk for contracting
endophthalmitis following phacoemulsification cataract surgery. [2] In 2013 the European Society of
ed

Cataract and Refractive Surgeons (ESCRS) have published guidelines on prevention and treatment of
post-operative endophthalmitis.[28] According to this source, it is recommend performing surgical
procedures in specially prepared operating theaters (proper air-flow design, sterile and/or single-used
equipment), use of hand washing with an antiseptic soap solution, mask, gowning and sterile gloves.
pt

Antisepsis of the periocular skin area, cornea and conjunctival sac with topical povidone–iodine is
mandatory. The 5% - 10% povidone-iodine solution should be left in place at the skin surface to act for at
least 3 minutes. In case of any contraindications (allergy or hyperthyroidism), the 0.05% solution of
ce

chlorhexidine can be used instead. For conjunctiva and cornea antisepsis 5% povidone-iodine solution
should be left in the conjunctival sac for at least 3 min. It is important not to use povidone iodine
solution containing a detergent as it irreversibly coagulates the cornea. ESCRS guidelines recommends
applying 1mg cefuroxime in 0.1ml saline (0.9 per cent) by intra-cameral injection at the end of
Ac

surgery.[28]
In 2012 specific commercial cefuroxime sodium at the necessary concentration (0.1 mg/mL) for
intracameral use called Aprokam® (Laboratoires Théa, Clermont-Ferrand, France) received approval by
the European Medicines Agency (EMA) and was introduced to the European market. It is now officially
approved for intracameral antibioprophylaxis of post-operative endophthalmitis after cataract surgery in
24 European countries. Each vial contains 50 mg of cefuroxime to be reconstituted with 5 ml of saline
solution and administered in the amount of 0.1ml into the anterior chamber at the end of cataract
surgery. As a broad-spectrum antibiotic, it covers most gram-positive and gram-negative organisms
commonly associated with postoperative infectious endophthalmitis: staphylococci and streptococci
(except MRSA, MRSE and Enterococcus faecalis), Gram-negative bacteria (except Pseudomonas

Information Classification: General

 aeruginosa) and P. acnes. In Sweden intracameral cefuroxime has been commonly used since 1999 (90%
in 2012) and informally recommended by the National Cataract Registry and the Swedish
Ophthalmological Society. In France, the Health Ministry-governed regulatory Agence Française de
Sécurité Sanitaire des Produits de Santé in 2011 released official national guidelines that intracameral
cefuroxime at the end of the surgery is strongly recommended. In 2011 it was used by 40% of surgeons.
In the United Kingdom, the Royal College of Ophthalmologists leaves the decision of intracameral
antibiotic use to the surgeon, and the Scottish Intercollegiate Guidelines Network recommends
intracameral antibiotics in cataract surgery. The surveys from 2010 have shown that it was used by 61%
of surgeons then. In the Netherlands, the Dutch Ophthalmological Society recommends cefuroxime in

t
high-risk cases only. In 2010 it was used in 27% of cases. In Italy, there are no national guidelines but

ip
surgeons tend to follow the ESCRS guidelines. In 2011 intracameral antibiotics were used in 41% of
procedures, either cefuroxime (52%) or vancomycin (48%). In other European countries lacking national
guidelines surgeons also tend to follow the ESCRS recommendations.[29]

cr
The use of topical antibiotics differs in many European countries. In Sweden and Denmark
topical antibiotics before and after cataract surgery are not recommended in standard cases by national
guidelines and most surgeons avoid using them. Although post-operative topical antibiotics are used in

us
majority of European countries for 5-7 days, their preoperative use has declined in recent years. For
example, French national guidelines do not recommend to use topical antibiotics before surgery, and
many surgeons in Poland and in Germany stopped this practice in recent years.
an
ESCRS guidelines argue that topical antibiotics preoperatively and/or postoperatively do not
confer a clear benefit over chlorhexidine or PVI preoperatively and intracameral antibiotics injected at
the close of surgery.[28] However, chlorhexidine has not yet been investigated adequately as prophylaxis
for endophthalmitis.[30] The choice of postoperative antisepsis is at present a decision of the surgeon,
M
after evaluating the postoperative state of a patient and assessment of complications occurred.
Intravenous antibiotic prophylaxis is not recommended as in the non-inflamed eye antibiotic weakly
penetrate to the globe. Oral antibiotic prophylaxis is recommended only in cases of coexisting severe
atopic disease when the lid margins are more frequently colonized with S. aureus. After a penetrating
ed

injury the same antibiotic should be administered systemically, as well as by the intravitreal route.[28]
The study by Grzybowski et al. overviewed the current practice patterns around the world,
including the US, Canada, Australia/New Zealand, Japan, China, India, Indonesia, South Africa, Argentina,
Russia, Sweden and Mexico.[31] They noted that the reported endophthalmitis rates were generally
pt

comparable despite the wide variations in prophylaxis techniques. For example, preoperative antibiotics
were infrequently used in Australia/New Zealand, India, South Africa, Russia, and Mexico. These nations
did not appear to have substantially higher endophthalmitis rates than the nations that do use
ce

preoperative antibiotics.
One major area of difference is the use of intracameral antibiotics. The best available evidence
regarding intracameral antibiotics is the ESCRS randomized clinical trial, which reported reduced
endophthalmitis rates associated with intracameral cefuroxime. [2] However, there have been several
Ac

criticisms of the ESCRS study. The rates of endophthalmitis in eyes not randomized to receive
intracameral cefuroxime were relatively high (approximately 0.2%), which may have exaggerated the
apparent treatment benefits.
In addition, the investigators allowed multiple different surgical techniques and used topical
levofloxacin, rather than a newer fourth-generation fluoroquinolone such as moxifloxacin, which also
may have affected the outcomes.[32, 33] Of note, a prospective cohort study from India, published in
2015, of 15,122 cataract surgeries reported no significant difference in endophthalmitis rates associated
with the use of intracameral cefuroxime.[34]
Notably, the endophthalmitis rate in countries where intracameral antibiotics are rarely used,
like Mexico, China, Japan, and Russia, are similar to countries, where intracameral antibiotics are used

Information Classification: General

 very often, like Sweden, Indonesia, Australia and New Zealand. In most nations where intracameral
antibiotics are used, topical antibiotics are also used, usually both pre- and post-operatively. Therefore,
intracameral antibiotics are often used not as an alternative to topical antibiotics, but as a
supplement.[35]

5. Intracameral antibiotics for endophthalmitis prevention during cataract surgery

Intracameral (IC) antibiotics for endophthalmitis prophylaxis (ICAP) during cataract surgery are used as a
component of irrigation fluid or a bolus administered at the conclusion of surgery. They are used both

t
with and without topical antibiotics. Some cataract surgeons have used IC antibiotics for decades. Gills

ip
popularized using dilute vancomycin and gentamycin mixed into irrigating fluid in the 1990s. In vitro, at
the concentration of vancomycin used clinically in irrigation solution, vancomycin is unlikely to kill
susceptible bacteria given its 70-minute half-life in the anterior chamber. Furthermore, the use of

cr
antibiotics in irrigation fluid has decreased, while use as a bolus at the conclusion of surgery has
increased.[36] [37] Therefore, this review will focus on the administration of antibiotics as a bolus at the
conclusion of surgery.

us
The literature regarding ICAP in cataract surgery consists of predominantly large retrospective series
and two randomized controlled trials. Endophthalmitis occurrence is the primary outcome of interest in
these studies and no studies using anterior chamber contamination rate at a proxy for endophthalmitis
an
risk were identified. The most common antibiotics studied for IC use are cefuroxime, moxifloxacin and
vancomycin.

5.1 Pharmacology
M
The primary measure of antibiotic activity of an antimicrobial agent is the minimum inhibitory
concentration (MIC). The MIC is the lowest concentration of an antibiotic that completely inhibits the
growth of a microorganism in vitro. MIC values are determined in vitro by incubating bacteria with
increasing concentrations of the antibiotic of interest. The categorization of the MIC value as
ed

susceptible, intermediate, and resistant, is carried out using standards developed by organizations such
as the Clinical and Laboratory Standards Institute (CLSI) in the United States, and the Committee on
Antimicrobial Susceptibility Testing (EUCAST) in Europe. The break point MIC is the cut off concentration
for a drug, delineating the designation of resistant or susceptible, and these values are continually
pt

reviewed and revised to reflect clinical outcomes and evolving bacterial resistance. There can be
discrepancies between these two organizations, and significant limitations in applicability to
ophthalmology. While the MIC is a good indicator of the potency of an antibiotic, it tells us nothing
ce

about the time course of antimicrobial activity. [38] [39]

Pharmacokinetic parameters describe the time course of drug levels in body fluids and include
the peak level, the trough level and the area under the concentration time curve. These parameters
quantify the antibiotic level time course but they do not describe the killing activity of the antibiotic.
Ac

Pharmacodynamics describes the relationship between antimicrobial concentrations and the

antimicrobial effect. There are three pharmacodynamic properties of antibiotics that best describe
killing activity. These are time dependence, concentration-dependence and persistent effects. Some
antibiotic classes exhibit time dependent killing; the inhibitory effect of the drug is primarily determined
by the length of time the concentration is greater than the MIC. Other antibiotics have concentration
dependent killing; high drug concentration at the target site primarily determines the effectiveness of
the drug. Of the drugs commonly used for intracameral prophylaxis, vancomycin and cefuroxime are
considered time dependent with vancomycin demonstrating moderate to prolonged persistent effects
and cefuroxime demonstrating minimal persistent effects. Moxifloxacin is concentration dependent and
exhibits prolonged persistent effects.[40]

Information Classification: General

 5.2 IC pharmacology:
An antibiotic’s pharmacodynamic and pharmacokinetic characteristics in the anterior chamber are
different than when administered systemically. An example best illustrates the significance of these
differences. The peak serum concentration of cefuroxime is 0.039 ug/ml when administered at the usual
adult dose (750-1,500 mg), and it is administered multiple times a day over several days. When
administered intracamerally, the concentration of cefuroxime is 2.742 mg/ml thirty seconds after
administration (70 times higher concentration), decreases by a factor of four in one hour, and is given a
single time.[41]

t
Evaluating pharmacokinetics in ophthalmology is difficult for technical and ethical reasons.

ip
Ideally serial samples of aqueous fluid taken at different time points would be obtained to determine
drug elimination and half-life after cataract surgery. Entering the eye repeatedly increases patient risk
and is inconvenient; additionally the small volume of the anterior chamber after cataract surgery

cr
(approximately 0.4 ml) relative to the aqueous sample needed for study (often 0.1ml) introduces
significant error. One way to avoid these limitations is to take a single sample from each patient; for
example taking aqueous samples 30 seconds after drug administration from a number of patients and

us
60 minutes after administration from a different set of patients Using this paired sample technique the
half-life of several antibiotics in the anterior chamber has been calculated. Gentamycin’s half-life in the
anterior chamber is 52 minutes, cefuroxime concentration decreased by a factor of 4 one hour after
an
administration. [41, 42] The rapid clearance of antibiotics from the anterior chamber, therefore, can
limit the usefulness of some antibiotics. [42]

5.3 Detailed information regarding IC vancomycin

M
Vancomycin is a glycopeptide antibiotic that inhibits the late stages of cell wall synthesis in dividing
bacteria. Vancomycin has significant activity against gram-positive organisms, including penicillin
resistant species, and demonstrates nearly no activity against gram-negative organisms in vitro.
Vancomycin resistant enterococci (VRE) exist worldwide and vancomycin resistant staphylococcus
ed

aureus (VRSA) have been reported. While considered a time dependent antibiotic, concentration also
plays an important role. For example, vancomycin is bactericidal at relatively low concentrations, twice
the MIC, for some bacteria such as staphylococci, while for other species such as Enterococus it is not
considered bactericidal even to susceptible organisms; the minimal bactericidal concentration (MBC) is
pt

32 times the MIC.[43] Used as an intracameral bolus, 1 mg in 0.1 ml, the aqueous concentration of
vancomycin is 5,385 mg/L one minute after administration and 41.1 mg/L 18-24 hours later.
Intracameral vancomycin in cataract surgery is unlikely to promote vancomycin resistance.[44] This is in
ce

contrast to evidence that topical antibiotic use does promote antibiotic resistance, which is not
surprising given the sterile nature of the intraocular environment compared with the ocular surface,
which is colonized, by bacteria.[45]
A series of 11 eyes in 6 patients reported postoperative hemorrhagic occlusive retinal vasculitis
Ac

(HORV) in 2015 after routine phacoemulsification with prophylactic intracameral vancomycin. The
clinical characteristics of this disease were further described in 36 eyes in 2017 and include a delayed
onset (mean 8 days) severe painless retinal vasculitis with poor outcomes: 61% of eyes had VA of 20/200
or worse and 56% of eyes progressed to neovascular glaucoma. The etiology is suspected to be an
immune reaction to vancomycin (type three delayed hypersensitivity).[46, 47] In 2016 the American
Academy of Ophthalmology added a recommendation against using intracameral vancomycin for
routine endophthalmitis prophylaxis to its Cataract in the Adult Eye Preferred Practice Pattern.[48]

5.4 Detailed information regarding IC cefuroxime

Information Classification: General

 Cefuroxime is a cephalosporin antibiotic, these antibiotics contain a B-lactam ring and inhibit bacterial
growth by disrupting cell wall synthesis, like other B-lactam drugs such as penicillin. The cephalosporins
are divided into five groups, loosely based on antimicrobial activity. First generation cephalosporins
have significant activity against gram-positive bacteria and less activity against gram negative bacteria.
Second generation cephalosporins have increased activity against gram negative bacteria while
maintaining varying degrees of activity against gram positive bacteria, and so on. Cefuroxime’s MIC
50%/90% for Staphylococcus epidermidis is 2/>32 ug/ml, for Staphylococcus aureus (methicillin
sensitive) it is 1/2 ug/ml, and for Streptococcus viridans 0.12/0.50 ug/ml. Methicillin resistant
Staphylococcus aureus is resistant to cefuroxime, and the MIC 90% for Staphylococcus epidermidis is

t
high, though similar to most other cephalosporins. The new fifth generation cephalosporins have

ip
excellent coverage and MIC 90% of less than 2 ug/ml for these organisms. Coverage is poor for some
gram-negative organisms such as Pseudomonas and limited for Enterococci; even the new 5th
generation ceftaroline has a MIC 90% of 128 ug/ml for Pseudomonas.[49, 50] No reports of the fifth

cr
generation cephalosporins, ceftobiprole and ceftaroline, used intracamerally were identified.
After appearing well tolerated in a rabbit model, a nonrandomized prospective study to
evaluate the pharmacokinetics and safety of intracameral cefuroxime in human subjects was conducted.

us
The dose used in the study was 1 mg, in 0.1 ml of 0.9% saline injected as the last step in routine cataract
surgery. One case of endophthalmitis caused by a cefuroxime sensitive strain was reported after more
than 32,000 surgeries. No difference in safety as evaluated by endothelial cell count, anterior chamber
an
inflammation (laser flare intensity), and cystoid macular edema was found between the groups. [41]
Given the reasonable concern of IgE mediated hypersensitivity the study used skin-prick tests identify
patients at risk. The authors concluded that IgE-mediated hypersensitivity to cefuroxime is rare, and in
patients with hypersensitivity who were pre-treated with oral antihistamine, no adverse effects were
M
observed.
Despite the high MIC 90% for Staphylococcus epidermidis, a large observational study found
that cefuroxime worked well against Staphylococcus epidermidis; in the untreated group it was the most
common cause of endophthalmitis and was eliminated as a cause completely in the treated group.
ed

Enterococci and gram-negative species became the major causes in the treated group, and these
organisms were resistant to cefuroxime. [51] [52] Many of these organisms were more sensitive to the
fifth generation cephalosporin ceftaroline; the MIC 50% for this drug against some Enterococci species is
2 ug/ml and for Serratia species is 0.06 ug/ml.[53] The multicenter ESCRS study was partially masked
pt

and randomized and included approximately 16,000 patients. It found a 5-fold reduction in POER using
IC cefuroxime. The investigators found the results significant enough to stop the study and report the
results prior to study completion. [54] Many retrospective case series have evaluated cefuroxime, and
ce

the majority have shown decreased POER, though some found the effect to be moderate and less than a
the 5-fold reduction found in the ESCRS study. [8, 13]

5.5 Detailed information regarding IC moxifloxacin

Ac

Moxifloxacin is a quinolone derivative. It is considered a fourth-generation fluoroquinolone and inhibits

the bacterial enzymes DNA gyrase and topoisomerase IV. This prevents the bacteria from synthesizing
DNA and results in cell death. Note that this is a significantly different mechanism of action than both
vancomycin and cefuroxime, which inhibit cell wall synthesis in dividing bacteria. With some exceptions,
DNA gyrase is the main target in gram-negative organisms, and topoisomerase IV the target in gram-
positive organisms.
Fluoroquinolones are most active against gram-negative bacilli, activity against streptococci and
anaerobes is more variable. Against these organisms some quinolones such as ciprofloxacin and
ofloxacin have limited activity while others such as gatifloxacin and moxifloxacin have greater
activity.[55] In vitro high dose moxifloxacin (1,500 ug/ml) most effectively eliminated bacteria cultured

Information Classification: General

 from actual from endophthalmitis cases more effectively than vancomycin and cefuroxime. [56] In this
study, as expected, moxifloxacin performed well against Pseudomonas, and still maintained activity
against MRSA, MRSE and other gram-positive species. [57] The concentration of moxifloxacin in the
anterior chamber is dramatically higher than MIC 90% values for nearly every bacterial species. For
example, the MRSA MIC 90% is 4 ug/ml, the anterior chamber concentration is 375 times this amount.
The half-life in the anterior chamber is approximately one hour. [58]
Understanding drug percentages, doses and concentrations can be confusing especially for
intracameral use. Moxifloxacin is manufactured as a 0.5% solution, which means the concentration is 5
mg/mL. If approximately 0.3-0.4 ml of the solution was injected into the anterior chamber it would fill

t
the chamber and produce a concentration of 5 mg/mL. Single use 0.5% moxifloxacin for intracameral

ip
use is available in some countries (Auromox; Aurolab, Tamil Nadu, India). If unavailable, such as in the
US, branded 0.5% Vigamox eye drops can be taken straight from the bottle and used intracamerally. The
medication can be administered as a 0.1 ml bolus at the conclusion of surgery, making the dose 0.5

cr
milligrams and the resulting concentration in the anterior chamber 1.5 mg/mL. While not exact,
multiplying the dose in mg by three approximates the concentration in the anterior chamber when a 0.1
ml bolus is used. Alternatively, the medication can be diluted; 3 ml of moxifloxacin diluted with 7 ml of

us
BSS produces a 0.15% (1.5 mg/mL) solution. If the moxifloxacin is diluted, the entire chamber can be
filled with medication, which could be easier to do than injecting a 0.1 ml bolus and provide a more
consistent concentration in the anterior chamber at the conclusion of surgery. Experimentally, no
an
difference in anterior chamber concentration was found between these two methods of
administration.[58] Importantly if using moxifloxacin designed for topical use, care should be taken to
make sure that intracameral use is appropriate, for example the moxifloxacin solution Avelox (Bayer)
has a low pH and should not be used in the eye.
M
Endothelial cell count, inflammation, corneal pachymetry, corneal edema, visual acuity and
macular thickness did not appear to be adversely affected by IC moxifloxacin.[56, 59] Two year follow up
of similar safety parameters with the exception of retinal thickness, also found no difference between
the IC moxifloxacin and the control group.[60] These articles did not evaluate “high” concentration
ed

moxifloxacin, 1.5 mg/ml that is most effective against Pseudomonas species and Staphylococcus aureus.
One study using high dose moxifloxacin reportedly demonstrated no change in corneal thickness or
endothelial cell count, but the original article could not be located.[57] In vitro, concentrations of
greater than 0.5mg/mL reduced endothelial cell viability.[61] In clinical practice, large numbers of
pt

patients have received the high dose moxifloxacin without noticeable detriment to the cornea.[62]
Intracameral moxifloxacin prophylaxis resulted in a lower endophthalmitis rate in a large, six
hundred thousand case, retrospective clinical registry study conducted in India. A six-fold reduction of
ce

endophthalmitis in patients who had phacoemulsification surgery was found. The etiology of the
endophthalmitis was different in patients who received IC moxifloxacin. The percentage of culture
negative cases increased from 63% to 83% in the IC moxifloxacin group and CoNS decreased from 20%
to 7%. In this study, no cases of TASS or corneal endothelial injury were felt to have resulted from IC
Ac

moxifloxacin, though this was not rigorously tested.[62] Other studies found a reduction of
endophthalmitis rates after adopting IC moxifloxacin.[63] A 3640 eye prospective randomized trial
recently reported from Brazil found an POER of 0.05% in the IC moxifloxacin and 0.38% in the control
group.[64]

6. Weighing the evidence for ICAP in cataract surgery

Intracameral use of antibiotics in cataract surgery likely reduces the rate of post-operative
endophthalmitis. The decision to routinely use ICAP, therefore, depends on safety profile, cost,
availability, and magnitude of effect. The risk of promoting bacterial resistance with routine ICAP has
been raised, though it is likely low because of generally one-time application and use inside the eye

Information Classification: General

 would result in elimination of bacteria or their proliferation (endophthalmitis). Small amounts of
antibiotic leaking out of the wound could theoretically produce some resistance. This is a contrast to
repeated topical prophylactic antibiotic use, such as with intravitreal injection, in which antibiotic use
selects for more virulent antibiotic resistant organisms to colonize the ocular surface.[45]
An additional concept that is important to consider when using an additional medication to
prevent a rare event is the number needed to treat. For example, if the POER is 0.06% and ICAP lowers
the POER to 0.02%, the medication would have to be administered to 2,500 patients to prevent
endophthalmitis one time. If the POER without ICAP is lowered to 0.03% the number needed to treat
rises dramatically to 10,000 patients. As has been emphasized previously, the risk / benefit ratio

t
depends heavily on the POER achieved without the use in ICAP.[65] In some countries, such as Japan,

ip
the PEOR rate without adoption of ICAP is 0.03%, reducing the impetus to adopt ICAP.[66]
A cost analysis of patients primarily undergoing manual small incision cataract surgery with and
without IC moxifloxacin estimated that the cost of administering the medication was fully offset by

cr
savings resulting from the decreased endophthalmitis in the group receiving ICAP. The NNT to achieve
the cost parity demonstrated in this study was 1,500.[67] Cost analysis is highly variable between
nations, the 0.15 cent cost / dose of IC moxifloxacin reported in the Indian study cited above in unlikely

us
realistic in North America. Despite this, a cost analysis from the USA estimated that at a cost of <$22 /
dose, IC moxifloxacin is cost effective or cost saving from a societal perspective, even with concurrent
topical antibiotic use. Topical antibiotics have little demonstrated efficacy generally, and when
an
intracameral antibiotics are used may not provide an additional benefit.[54, 68]
The availably of commercial antibiotics for IC use and therefore the need for “homemade” or
compounded IC antibiotics is highly variable. Intraocular cefuroxime (Aprokam, Thea) is available in
many European countries. An Indian company (Promax, Aurolab) produces moxifloxacin solution for
M
intracameral use. This is available in India and exported to several other countries, mostly in Asia and
the Middle East. In many regions of the world no commercial preparation exists.[69]

6.1 Further safety considerations

ed

Except for vancomycin’s association with HORV, no predictable injury to the eye has been reported with
ICAP. This does not mean serious vision and life-threatening complications have not occurred. In a 2014
survey of ASCRS members, 6% reported a complication with “home-made” intracameral antibiotics,
including toxic anterior segment syndrome and endothelial injury. This is in contrast to studies using
pt

antibiotics manufactured for IC use, which did not find cases of TASS or endothelial injury attributable to
ICAP.[37] A survey of ophthalmologists in India (All India Ophthalmological Society) found that in 5% of
eyes after ICAP, TASS or endothelial injury occurred, and this was attributed to the use of commercially
ce

available moxifloxacin. [70] In the ICAP literature it is difficult to evaluate non-endophthalmitis adverse
events because large series often do not report this data. A dilution error of cefuroxime caused severe
toxicity in 16 patients operated on consecutively, including permanent loss of vision. Toxic posterior
segment syndrome has been reported in patients who received compounded triamcinolone-
Ac

moxifloxacin. Other case series describing complications after ICAP exist, including contamination
causing endophthalmitis.[71, 72] [73]
Concern regarding allergic reaction is commonly considered clinically when using a
cephalosporin because of the known cross-reactivity with penicillin allergy and high frequency of
reported penicillin allergy. The actual cross-reactivity with penicillin is less than the traditionally thought
10%. A prospective study found a 6% cross-reactivity rate with IgE mediated penicillin allergy (a small
minority of all patients who report penicillin “allergy”) and rates less than 1% were found in
observational studies.[74, 75] While anaphylaxis has been reported multiple times following IC
cefuroxime use, no deaths have been reported.[76] Anaphylactic shock has also been reported after
topical moxifloxacin administration pre-operatively. [77] These are case reports and the incidence of

Information Classification: General

 serious allergic reactions is not known, though likely to be low. When used intracamerally, patients with
IgE mediated hypersensitivity reportedly tolerated IC cefuroxime without incident after pretreatment
with oral antihistamine. In patients with anaphylaxis to penicillin or cephalosporin allergy, consideration
should be given to using moxifloxacin as an alternative given the rare risk of anaphylaxis.

6.2 Further efficacy considerations

The preponderance of ICAP studies report lower POER after ICAP adoption. Further discussion is needed
to contextualize the significance of these findings. Recurrent criticisms of the ICAP literature include: (1)
a high POER in patients not receiving ICAP, and the ICAP POER being achieved in large series without IC

t
antibiotics (2) decrease in POER over time, prior to the initiation of ICAP, and (3) the lack of randomized

ip
controlled trials.[65, 78] Additional large scale randomized controlled trials are likely to be rare for
economic, regulatory and possibly ethical reasons.[79] There is a large randomized controlled trial
ongoing in the United States evaluating IC moxifloxacin, which will be the first in North America. The

cr
many large observational studies from many regions of the world make up the majority of the
evidence.[80] Some of the concerns related to ESCRS Study were addressed, to the extent possible in a
large retrospective clinical registry, by Haripriya et al. The report analyses many cases (600,000) over a

us
short time period and the POER reduction demonstrated at one hospital was duplicated in the nine
other hospitals in the system. Additionally, the PEOR rate prior to ICAP was already low.[70] It should be
noted in the ESCRS study that clear corneal incisions significantly increased the odds ratio (OR = 5.88) of
an
developing endophthalmitis. Furthermore, definitive wound closure by suturing was not reported and
no subsequent prospective studies have compared sutured and unsutured corneal incisions. Metanalysis
and systematic review articles estimate a 2.5 fold reduction of POER to a rate of about 0.03% using
ICAP.[80] A minority of studies have not found an effect, but they lacked power to defect a fairly
M
substantial difference.[34, 81] Cefuroxime and moxifloxacin both appear to be effective. As mentioned,
cefuroxime is not effective against some bacteria. The culture positive endophthalmitis cases have
reflected this after its widespread adoption in some regions; there will be some baseline
endophthalmitis rate with this medication because of gram-negative organisms and Enterococci.
ed

Moxifloxacin could be more effective than cefuroxime, there is support for this in vitro and in the
extremely low endophthalmitis rates reported in large observational studies. Though endophthalmitis
has been reported after IC moxifloxacin caused by resistant Staphylococcus epidermidis.[82]
pt

7. Povidone Iodine
Iodine has been recognized as an effective bactericide for hundreds of years. Clinically, iodine is used as
a complex of the polymer polyvinylpyrrolidone (PVP) and iodine “povidone-iodine” (PI) to increase
ce

water solubility and decrease irritant and allergic reactions.[83] In addition to use as a surgical scrub for
skin disinfection and in preparation for ophthalmic surgery or intraocular injection, PI is also used in
more limited applications such as to treat infectious keratitis, keratoconjunctivitis, endophthalmitis,
and in ophthalmia neonatorum prophylaxis.[84-86] PI has been studied extensively in
Ac

the ophthalmic setting, application of 5-10% PI solution to the eye surface and lids three minutes prior
to cataract surgery is supported by level I evidence. [87]
PI acts on a variety of bacteria, fungi, protozoa, and viruses.[88] The delivery of diatomic free iodine
(I2) directly to the target cell surface is thought to be the crucial event of antimicrobial action.[89] For
bacteria, PI targets the cytoplasmic membrane and cytoplasm, with killing taking place in a matter of
seconds.[90] Free iodine iodinates and oxidizes proteins, enzymes, and other molecules essential for
biologic viability.[91] PI is bactericidal against drug-resistant bacteria.[92, 93] Importantly, unlike
antibiotics, PI solution does not have a known specificity for microorganisms and can be expected to act
on host cells.

Information Classification: General

 PI toxicity in the ophthalmic setting has been studied in vitro, in animal models, and in clinical
studies. Repetitive 0.25% PI irrigation during cataract surgery was well tolerated by both the epithelial
and endothelial cells of the cornea. In vitro, 0.05% PI was not toxic to cultured bovine endothelial cells
with 12 hours of exposure. [94] In a rabbit model, intravitreal injections of 0.1 mL 0.1% and 0.3% PI were
found to be tolerable by electroretinography and histological examination.[95]
There are no randomized controlled trials of PI that use endophthalmitis rate as the primary end
point. In a large, open-label nonrandomized parallel trial, Speaker and Menikoff found that 5% PI
applied to conjunctiva before surgery reduced endophthalmitis rates from 0.24% to 0.06%.[96] Studies
evaluating concentration, dose, and other aspects of PI application have used the presence and

t
concentration of bacteria on the conjunctiva and in the anterior chamber as proxy measures for reduced

ip
endophthalmitis risk.[97] The reasons for this are the infrequent occurrence of endophthalmitis and
evidence implicating ocular surface flora as the cause of postoperative endophthalmitis.[98]
Shimada and coworkers evaluated anterior chamber contamination rates after repetitive

cr
preoperative and intraoperative surface irrigation of 0.25% PI during cataract surgery in Japan. Topical
and intravenous antibiotics were used, and the ocular surface was disinfected with 0.25% PI. The
experimental arm of the study yielded a 0% anterior chamber contamination rate in the 202 eyes

us
studied.[94] A similar study using repetitive 0.025% PI irrigation also achieved a 0% anterior chamber
contamination rate in 100 eyes.[99] In both the studies, the reduction of anterior chamber
contamination was significant compared with the topical BSS irrigation controls. In Japan, approximately
an
7% of cataract surgeons use repetitive irrigation with 0.25% PI, and use is increasing at academic centers
(Dr. Shimada, personal communication). No significant epithelial injury was observed, and there was no
change in endothelial cell count. When 0.25% PI is applied in this way, the concentration in the anterior
chamber at the end of surgery is 0.008%.
M
Shimada and coworkers demonstrated efficacy with 0.25% and 0.025% PI using dilute repetitive PI
application in two randomized trials. These studies achieved a combined anterior chamber
contamination rate of 0% in 302 eyes compared with a rate of approximately 5% in the BSS irrigation
control groups. Adjunctive antisepsis measures in these studies included a topical fluoroquinolone,
ed

intravenous antibiotic, and single application of dilute PI in the control group. Some of these measures,
such as the use of intravenous antibiotics, are not commonly used worldwide. Nonetheless, this
technique produced the largest series of anterior-chamber-culture negative patients ever reported.
pt

8. Expert opinion
Despite the decrease in endophthalmitis rate over the last 50 years, and increased understanding of its
pathogenesis, there are still major gaps in understanding this condition. The reported anterior chamber
ce

contamination rate after cataract surgery without the use of dilute PI has varied widely, large (>200 eye)
series report a range from 1.4%-13.7%.[100, 101] The relative importance of a sterile anterior chamber
at the end of surgery, compared to the risk of bacteria moving into the eye in the days after surgery is
also not known. The reduction in POERs after ICAP could suggest that achieving sterility at the
Ac

conclusion of surgery is the primary driver of a low endophthalmitis rate, these medications are not
present in bactericidal concentrations in the days following surgery. The lowest rate of anterior chamber
contamination ever reported was achieved without new antibiotics or new methods of administration,
but with dilute povidone iodine. Many of the barriers and concerns regarding ICAP could be potentially
reduced or eliminated with dilute povidone iodine. PI solution is already used in most cataract surgeries,
the diluted solution could be prepared with no additional cost by adding a drop or two to the BSS bottle,
and (if keeping the cornea wet in this way) no additional surgical steps are necessary. Using this anti-
septic technique does not require regulatory change or the approval of a new drug. Also, while
“homemade” the risk of a serious concentration error is minimal owing to the completely different color
of highly dilute PI solution compared with concentrated solution. Furthermore, this antiseptic technique

Information Classification: General

 could reduce the use of antibiotics. Inducible bacterial resistance has not been demonstrated using PI
solution. While with use of dilute PI to prevent endophthalmitis is not as widespread as intracameral
antibiotics, the pioneering work of Dr. Shimada and colleagues should be replicated and expounded
upon in different regions of the world. The safety data regarding dilute PI is equivalent to or more
robust than that of IC antibiotics, and this technique is not uncommonly used in academic centers in
Japan. If large series were reported to assess efficacy, dilute PI could be an excellent alternative to ICAP
to further reduce the POER.
The available evidence suggests ICAP lowers the POER, with the greatest effect demonstrated
during complicated cases and high baseline POER. When a commercial formulation is available and the

t
cost reasonable, its use should be considered. If the POER is suspected or known to be extremely low

ip
without ICAP (i.g. 0.3%), as has been reported in some large series, the decision is somewhat
equivocal.[102] [66] Further reduction of an already “acceptably” low POER (e.g. 0.07%) has been
reported. A universal recommendation to use ICAP in such situations with very a high number needed to

cr
treat cannot be made based on the literature; the decision must consider local realities such as the need
for compounding.[63] Of the two most commonly used IC antibiotics, moxifloxacin and cefuroxime,
there is no clear evidence that one is better than the other. Vancomycin is not recommended for routine

us
ICAP because of both the risk of HORV (extremely low) and concerns regarding the use of an
indispensable agent to treat multi-drug-resistant endophthalmitis as routine prophylaxis.[11] Further
research should clarify the role of topical antibiotics when ICAP is used. Topical antibiotics may not
an
provide an additional benefit, as has been suggested by several studies. In-fact, the practice of using
topical antibiotics routinely with ICAP added in complicated cases could be inverted; with ICAP used
routinely and topical antibiotics added in complicated cases. This could provide actual cost savings with
ICAP and potentially decrease the risk of inducing bacterial resistance. Finally, additional antibiotics
M
could be considered for intracameral use, such as fifth generation cephalosporins, which have an
improved spectrum of activity. If several large series reported comparable POER reduction with dilute PI
solution, routine ICAP could appear significantly less advantageous given the many desirable attributes
of PI solution.
ed

ICAP will continue to increase, and where available moxifloxacin will continue to be a popular choice for
ICAP given its inherent antimicrobial advantage over cefuroxime and tolerability demonstrated in very
large series from around the world. Although other antibiotics could be studied and used, with POE
pt

rates as low as 0.02% using moxifloxacin, new agents will probably not be introduced unless a problem
(such as a rare HORV like complication) is discovered. If not further studied and codified into
recommendations by cataract surgery professional organizations, there is a significant risk of continued
ce

wide speared topical antibiotic use after cataract surgery despite limited evidence for the efficacy of this
practice. Larger series from different regions will describe the use of dilute PI. If consistent with the
initial promising studies, use in clinic settings could increase in resource poor areas to further reduce
cost and more generally as an adjunctive measure to reduce contamination of the anterior chamber.
Ac

Although not likely in the next five-years, extremely low rates of POE could potentially be demonstrated
with dilute PI and no antibiotics at all. If this is indeed possible, the decreased use of antibiotics would
be massive given the number of cataract surgeries performed annually, making a concomitantly large
reduction in cost and risk of induced bacterial resistance.

Information Classification: General

 Funding
This paper was not funded

t
ip
Declaration of interest
A Grzybowski reports grants, personal fees and non-financial support from Bayer, non-financial support
from Novartis, non-financial support from Alcon, non-financial support from Thea, personal fees and

cr
non-financial support from Valeant, non-financial support from Santen, outside the submitted work.
The authors have no other relevant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or materials discussed in the

us
manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
an
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
M
ed
pt
ce
Ac

Information Classification: General

 References

t
1. Romero, P., et al., Intracameral cefazolin as prophylaxis against endophthalmitis in cataract

ip
surgery. J Cataract Refract Surg, 2006. 32(3): p. 438-41.
2. Endophthalmitis Study Group, E.S.o.C. and S. Refractive, Prophylaxis of postoperative
endophthalmitis following cataract surgery: results of the ESCRS multicenter study and

cr
identification of risk factors. J Cataract Refract Surg, 2007. 33(6): p. 978-88.
*This prospective randomized trial helped to popularize intracameral antibiotics generally, and
specifically cefuroxime. The study had several limitations, discussed in this review, but did

us
demonstrate a 5-fold decrease in endophthalmitis. Furthermore, it was the first (and only)
large scale multicenter prospective randomized study to evaluate intracameral antibiotics.
3. Yu-Wai-Man, P., et al., Efficacy of intracameral and subconjunctival cefuroxime in preventing
an
endophthalmitis after cataract surgery. J Cataract Refract Surg, 2008. 34(3): p. 447-51.
4. Garat, 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(4): p. 637-42.
5. Garcia-Saenz, M.C., et al., Effectiveness of intracameral cefuroxime in preventing
M
endophthalmitis after cataract surgery Ten-year comparative study. J Cataract Refract Surg,
2010. 36(2): p. 203-7.
6. Barreau, G., 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(8): p. 1370-5.
ed

7. Friling, E., et al., Six-year incidence of endophthalmitis after cataract surgery: Swedish national
study. J Cataract Refract Surg, 2013. 39(1): p. 15-21.
8. Rodriguez-Caravaca, G., et al., Incidence of endophthalmitis and impact of prophylaxis with
cefuroxime on cataract surgery. J Cataract Refract Surg, 2013. 39(9): p. 1399-403.
pt

9. Beselga, D., et al., Postcataract surgery endophthalmitis after introduction of the ESCRS protocol:
a 5-year study. Eur J Ophthalmol, 2014. 24(4): p. 516-9.
10. Rahman, N. and C.C. Murphy, Impact of intracameral cefuroxime on the incidence of
ce

postoperative endophthalmitis following cataract surgery in Ireland. Ir J Med Sci, 2015. 184(2):
p. 395-8.
11. Lundstrom, M., E. Friling, and P. Montan, Risk factors for endophthalmitis after cataract surgery:
Predictors for causative organisms and visual outcomes. J Cataract Refract Surg, 2015. 41(11): p.
Ac

2410-6.
12. Creuzot-Garcher, C., et al., Incidence of Acute Postoperative Endophthalmitis after Cataract
Surgery: A Nationwide Study in France from 2005 to 2014. Ophthalmology, 2016. 123(7): p.
1414-20.
13. Daien, V., et al., Effectiveness and Safety of an Intracameral Injection of Cefuroxime for the
Prevention of Endophthalmitis After Cataract Surgery With or Without Perioperative Capsular
Rupture. JAMA Ophthalmol, 2016. 134(7): p. 810-6.
14. Lundstrom, M., et al., Evidence-based guidelines for cataract surgery: guidelines based on data
in the European Registry of Quality Outcomes for Cataract and Refractive Surgery database. J
Cataract Refract Surg, 2012. 38(6): p. 1086-93.

Information Classification: General

 15. Colleaux, K.M. and W.K. Hamilton, Effect of prophylactic antibiotics and incision type on the
incidence of endophthalmitis after cataract surgery. Can J Ophthalmol, 2000. 35(7): p. 373-8.
16. Cooper, B.A., et al., Case-control study of endophthalmitis after cataract surgery comparing
scleral tunnel and clear corneal wounds. Am J Ophthalmol, 2003. 136(2): p. 300-5.
17. Aaberg, T.M., Jr., et al., Nosocomial acute-onset postoperative endophthalmitis survey. A 10-year
review of incidence and outcomes. Ophthalmology, 1998. 105(6): p. 1004-10.
18. Safneck, J.R., Endophthalmitis: A review of recent trends. Saudi J Ophthalmol, 2012. 26(2): p.
181-9.
19. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy

t
and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis.

ip
Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol, 1995. 113(12): p. 1479-96.
20. Mollan, S.P., et al., Postcataract endophthalmitis: incidence and microbial isolates in a United
Kingdom region from 1996 through 2004. J Cataract Refract Surg, 2007. 33(2): p. 265-8.

cr
21. Pijl, B.J., et al., Acute endophthalmitis after cataract surgery: 250 consecutive cases treated at a
tertiary referral center in the Netherlands. Am J Ophthalmol, 2010. 149(3): p. 482-7 e1-2.
22. Han, D.P., et al., Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis

us
Vitrectomy Study. Am J Ophthalmol, 1996. 122(1): p. 1-17.
23. Cheng, J.H., et al., Acute endophthalmitis after cataract surgery at a referral centre in Northern
Taiwan: review of the causative organisms, antibiotic susceptibility, and clinical features. Eye
(Lond), 2010. 24(8): p. 1359-65.
an
24. Anand, A.R., K.L. Therese, and H.N. Madhavan, Spectrum of aetiological agents of postoperative
endophthalmitis and antibiotic susceptibility of bacterial isolates. Indian J Ophthalmol, 2000.
48(2): p. 123-8.
M
25. Kunimoto, D.Y., et al., Microbiologic spectrum and susceptibility of isolates: part I. Postoperative
endophthalmitis. Endophthalmitis Research Group. Am J Ophthalmol, 1999. 128(2): p. 240-2.
26. Sheng, Y., et al., Endophthalmitis after cataract surgery in China, 1995-2009. J Cataract Refract
Surg, 2011. 37(9): p. 1715-22.
ed

27. Siak J, Aung Win MZ, Chee SP, Epidemiology and Treatment Trend of Endophthalmitis in Asia,
Endophthalmitis 1st edition, 2017, p. 29-44 (doi: 10.1007/978-981-10-5260-6)
28. Surgeons, T.E.S.f.C.a.R. ESCRS guidelines on prevention and treatment of endophthalmitis
following cataract surgery [webpage on the Internet]. . 2013.
pt

29. Behndig, A., et al., Endophthalmitis prophylaxis in cataract surgery: overview of current practice
patterns in 9 European countries. J Cataract Refract Surg, 2013. 39(9): p. 1421-31.
30. Grzybowski, A., et al., A review of preoperative manoeuvres for prophylaxis of endophthalmitis in
ce

intraocular surgery: topical application of antibiotics, disinfectants, or both? Curr Opin

Ophthalmol, 2016. 27(1): p. 9-23.
31. Grzybowski, A., et al., Endophthalmitis Prophylaxis in Cataract Surgery: Overview of Current
Practice Patterns Around the World. Curr Pharm Des, 2017. 23(4): p. 565-573.
Ac

32. Liesegang, T.J., Intracameral antibiotics: questions for the United States based on prospective
studies. J Cataract Refract Surg, 2008. 34(3): p. 505-9.
33. O'Brien, T.P., S.A. Arshinoff, and F.S. Mah, Perspectives on antibiotics for postoperative
endophthalmitis prophylaxis: potential role of moxifloxacin. J Cataract Refract Surg, 2007.
33(10): p. 1790-800.
34. Sharma, S., et al., Reevaluating intracameral cefuroxime as a prophylaxis against
endophthalmitis after cataract surgery in India. J Cataract Refract Surg, 2015. 41(2): p. 393-9.
35. RJ, O., Has the time come for all to routinely use intracameral antibiotic prophylaxis at the time
of cataract surgery? . Am J Ophthalmol 2016.

Information Classification: General

 36. JP., G., Filters and antibiotics in irrigating solution for cataract surgery. J Cataract Refract Surg.,
1991. 17: p. 385.
37. Chang, D.F., et al., Antibiotic prophylaxis of postoperative endophthalmitis after cataract
surgery: Results of the 2014 ASCRS member survey. J Cataract Refract Surg, 2015. 41(6): p. 1300-
5.
38. G, K., Breakpoints for intravenously used cephalosporins in Enterobacteriaceae--EUCAST and CLSI
breakpoints. Clin Microbiol Infect, 2008: p. 169-74.
39. Diene SM, A.C., Rolain JM, Raoult D., How artificial is the antibiotic resistance definition? Lancet
Infect Dis, 2017. 17: p. 690.

t
40. Quintiliani, R. Pharmacodynamics of Antimicrobial Agents: Time-Dependent vs. Concentration-

ip
Dependent Killing. July 2019. http://www.antimicrobe.org/h04c.files/history/PK-
PD%20Quint.asp.
41. Montan, P.G., et al., Prophylactic intracameral cefuroxime. Evaluation of safety and kinetics in

cr
cataract surgery. J Cataract Refract Surg, 2002. 28(6): p. 982-7.
42. Lehmann, O.J., et al., Half-life of intracameral gentamicin after phacoemulsification. J Cataract
Refract Surg, 1997. 23(6): p. 883-8.

us
43. G.R Dorowitx, G.L.M., Principles and Practice of Infectious Disease, ed. R.D. J.E. Bennett, M..J
Blaser. 2015, Philadelphia, PA: Elsevire/Saunders.
44. Libre PE, D.-L.P., Chin NX. , Intracameral antibiotic agents for endophthalmitis prophylaxis; a
an
pharmacokinetic model. J Cataract Refractive Surg 2003, 2003. 29: p. 1791-1794.
45. Storey, P., et al., The effect of prophylactic topical antibiotics on bacterial resistance patterns in
endophthalmitis following intravitreal injection. Graefes Arch Clin Exp Ophthalmol, 2016. 254(2):
p. 235-42.
M
46. Witkin, A.J., et al., Vancomycin-Associated Hemorrhagic Occlusive Retinal Vasculitis: Clinical
Characteristics of 36 Eyes. Ophthalmology, 2017. 124(5): p. 583-595.
47. Witkin, A.J., et al., Postoperative Hemorrhagic Occlusive Retinal Vasculitis: Expanding the Clinical
Spectrum and Possible Association with Vancomycin. Ophthalmology, 2015. 122(7): p. 1438-51.
ed

48. Olson RJ, B.-M.R., Huang Chen S, et al, Cataract in the Adult Eye Preferred Practice Pattern.
Ophthalmology, 2017. 124(2): p. 1-119.
49. G.R Dorowitx, G.L.M., Principles and Practice of Infectious Disease, R.D. J.E. Bennett, M..J Blaser,
Editor. 2015, Elsevire/Saunders: Philadelphia, PA.
pt

50. Zhanel, G.G., et al., Ceftaroline: a novel broad-spectrum cephalosporin with activity against
meticillin-resistant Staphylococcus aureus. Drugs, 2009. 69(7): p. 809-31.
51. Montan, P.G., et al., Prophylactic intracameral cefuroxime. Efficacy in preventing
ce

endophthalmitis after cataract surgery. J Cataract Refract Surg, 2002. 28(6): p. 977-81.
52. Perry, C.M. and R.N. Brogden, Cefuroxime axetil. A review of its antibacterial activity,
pharmacokinetic properties and therapeutic efficacy. Drugs, 1996. 52(1): p. 125-58.
53. Flamm, R.K., et al., Summary of ceftaroline activity against pathogens in the United States, 2010:
Ac

report from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance
program. Antimicrob Agents Chemother, 2012. 56(6): p. 2933-40.
54. Barry, P., et al., ESCRS study of prophylaxis of postoperative endophthalmitis after cataract
surgery: Preliminary report of principal results from a European multicenter study. J Cataract
Refract Surg, 2006. 32(3): p. 407-10.
55. G.R Dorowitx, G.L.M., Principles and Practice of Infectious Disease, ed. R.D. J.E. Bennett, M..J
Blaser. Philadelphia, PA: Elsevire/Saunders.
56. Arbisser, L.B., Safety of intracameral moxifloxacin for prophylaxis of endophthalmitis after
cataract surgery. J Cataract Refract Surg, 2008. 34(7): p. 1114-20.

Information Classification: General

 57. Libre, P.E. and S. Mathews, Endophthalmitis prophylaxis by intracameral antibiotics: In vitro
model comparing vancomycin, cefuroxime, and moxifloxacin. J Cataract Refract Surg, 2017.
43(6): p. 833-838.
58. Matsuura, K., et al., Comparison between intracameral moxifloxacin administration methods by
assessing intraocular concentrations and drug kinetics. Graefes Arch Clin Exp Ophthalmol, 2013.
251(8): p. 1955-9.
59. Lane, S.S., et al., Evaluation of the safety of prophylactic intracameral moxifloxacin in cataract
surgery. J Cataract Refract Surg, 2008. 34(9): p. 1451-9.
60. Cavalcanti Lira, R.P., et al., Long-term safety of intracameral moxifloxacin after cataract surgery.

t
J Cataract Refract Surg, 2017. 43(1): p. 139-140.

ip
*While retrospective, this study further supported the use of intracameral antibiotics in several ways.
The authors reported an extremely large series from a network of eye hospitals with similar
operations. Additionally, they demonstrated reproducibility, showing that individually and

cr
collectively the addition of intracameral moxifloxacin decreased the post-operative
endophthalmitis rate in ten different eye hosptials. Finally, the pre-intervention
endophthalmitis rate was reasonable (a criticism of the ESCRS study).

us
61. Haruki, T., et al., Comparison of toxicities of moxifloxacin, cefuroxime, and levofloxacin to
corneal endothelial cells in vitro. J Cataract Refract Surg, 2014. 40(11): p. 1872-8.
62. Haripriya, A., D.F. Chang, and R.D. Ravindran, Endophthalmitis Reduction with Intracameral
an
Moxifloxacin Prophylaxis: Analysis of 600 000 Surgeries. Ophthalmology, 2017. 124(6): p. 768-
775.
63. Matsuura, K., et al., Efficacy and safety of prophylactic intracameral moxifloxacin injection in
Japan. J Cataract Refract Surg, 2013. 39(11): p. 1702-6.
M
64. Melega, M.V., et al., Safety and efficacy of intracameral moxifloxacin for prevention of post-
cataract endophthalmitis: Randomized controlled clinical trial. J Cataract Refract Surg, 2019.
45(3): p. 343-350.
65. Schimel, A.M., E.C. Alfonso, and H.W. Flynn, Jr., Endophthalmitis prophylaxis for cataract
ed

surgery: are intracameral antibiotics necessary? JAMA Ophthalmol, 2014. 132(11): p. 1269-70.
66. Inoue, T., et al., Incidence of endophthalmitis and the perioperative practices of cataract surgery
in Japan: Japanese Prospective Multicenter Study for Postoperative Endophthalmitis after
Cataract Surgery. Jpn J Ophthalmol, 2018. 62(1): p. 24-30.
pt

67. Haripriya, A., et al., Efficacy of Intracameral Moxifloxacin Endophthalmitis Prophylaxis at Aravind
Eye Hospital. Ophthalmology, 2016. 123(2): p. 302-8.
68. Leung, E.H., et al., Intracameral moxifloxacin for endophthalmitis prophylaxis after cataract
ce

surgery: Cost-effectiveness analysis. J Cataract Refract Surg, 2018. 44(8): p. 971-978.

69. Haripriya, A. and D.F. Chang, Intracameral antibiotics during cataract surgery: evidence and
barriers. Curr Opin Ophthalmol, 2018. 29(1): p. 33-39.
70. Kelkar, A.S., et al., Antibiotic prophylaxis practice patterns for cataract surgery in India - Results
Ac

from an online survey. Indian J Ophthalmol, 2017. 65(12): p. 1470-1474.

71. Patel, S.B., N.K. Reddy, and Y.G. He, Toxic Posterior Segment Syndrome after Dropless Cataract
Surgery with Compounded Triamcinolone-Moxifloxacin. Retina, 2019.
72. Olavi, P., Ocular toxicity in cataract surgery because of inaccurate preparation and erroneous use
of 50mg/ml intracameral cefuroxime. Acta Ophthalmol, 2012. 90(2): p. e153- 4.
73. Cakir, M., et al., An outbreak of early-onset endophthalmitis caused by Fusarium species
following cataract surgery. Curr Eye Res, 2009. 34(11): p. 988-95.
74. Daulat, S., et al., Safety of cephalosporin administration to patients with histories of penicillin
allergy. J Allergy Clin Immunol, 2004. 113(6): p. 1220-2.

Information Classification: General

 75. Park, M.A., et al., Increased adverse drug reactions to cephalosporins in penicillin allergy patients
with positive penicillin skin test. Int Arch Allergy Immunol, 2010. 153(3): p. 268-73.
76. Moisseiev, E. and E. Levinger, Anaphylactic reaction following intracameral cefuroxime injection
during cataract surgery. J Cataract Refract Surg, 2013. 39(9): p. 1432-4.
77. Ullman, M.A., et al., Anaphylactic reaction secondary to topical preoperative moxifloxacin. J
Cataract Refract Surg, 2016. 42(12): p. 1836-1837.
78. Nentwich, M.M., et al., Incidence of postoperative endophthalmitis from 1990 to 2009 using
povidone-iodine but no intracameral antibiotics at a single academic institution. J Cataract
Refract Surg, 2015. 41(1): p. 58-66.

t
79. Javitt, J.C., Intracameral Antibiotics Reduce the Risk of Endophthalmitis after Cataract Surgery:

ip
Does the Preponderance of the Evidence Mandate a Global Change in Practice? Ophthalmology,
2016. 123(2): p. 226-31.
80. Naseri, A., R.B. Melles, and N.H. Shorstein, Intracameral Antibiotics in the Shadow of

cr
Hemorrhagic Occlusive Retinal Vasculitis. Ophthalmology, 2017. 124(5): p. 580-582.
81. Rudnisky, C.J., D. Wan, and E. Weis, Antibiotic choice for the prophylaxis of post-cataract
extraction endophthalmitis. Ophthalmology, 2014. 121(4): p. 835-41.

us
82. Chang, V.S., et al., Endophthalmitis following cataract surgery and intracameral antibiotic:
Moxifloxacin resistant Staphylococcus epidermidis. Am J Ophthalmol Case Rep, 2019. 13: p. 127-
130.
83.
an
Houang, E.T., et al., Absence of bacterial resistance to povidone iodine. J Clin Pathol, 1976. 29(8):
p. 752-5.
84. Isenberg, S.J., et al., Prospective, Randomized Clinical Trial of Povidone-Iodine 1.25% Solution
Versus Topical Antibiotics for Treatment of Bacterial Keratitis. Am J Ophthalmol, 2017. 176: p.
M
244-253.
85. Isenberg, S.J., L. Apt, and M. Wood, A controlled trial of povidone-iodine as prophylaxis against
ophthalmia neonatorum. N Engl J Med, 1995. 332(9): p. 562-6.
86. Otani K, S.H., Capsular bag irrigation using 0.025% povidone-iodine in balanced salt solution
ed

PLUS for the treatment of postoperative endophthalmitis. Int Ophthalmol., 2018. 38((6)): p.
2267-2268.
*This study is the first to report the unique ability of dilute concentrations of povidone iodine to
produce faster in vitro killing times than more conentrated solutions. For example, 0.25%
pt

povidione iodine solution has a killing time equal to or faster than 10% solution. This study
expanded the possible uses of povidione iodine solution to include repetiative application of
dilute solution.
ce

87. Ciulla, T.A., M.B. Starr, and S. Masket, Bacterial endophthalmitis prophylaxis for cataract
surgery: an evidence-based update. Ophthalmology, 2002. 109(1): p. 13-24.
88. Zamora, J.L., Chemical and microbiologic characteristics and toxicity of povidone-iodine
solutions. Am J Surg, 1986. 151((3)): p. 400-406.
Ac

89. Berkelman, R.L., B.W. Holland, and R.L. Anderson, Increased bactericidal activity of dilute
preparations of povidone-iodine solutions. J Clin Microbiol, 1982. 15(4): p. 635-9.
90. Fleischer, W. and K. Reimer, Povidone-iodine in antisepsis--state of the art. Dermatology, 1997.
195 Suppl 2: p. 3-9.
91. Chou, S.F., C.H. Lin, and S.W. Chang, Povidone-iodine application induces corneal cell death
through fixation. Br J Ophthalmol, 2011. 95(2): p. 277-83.
*Dr. Shimada, using frequent application of dilute povidone iodine solution reported the largest post
cataract surgery anterior chamber culture negative series to date. This technique has several
advantages related to the characteristics of povidone iodine, including: wide spectrum of activity,
including resistant organisms, lack or inducible resistance, low cost, and universal availability.

Information Classification: General

 92. Pelletier, J.S., et al., In vitro efficacy of a povidone-iodine 0.4% and dexamethasone 0.1%
suspension against ocular pathogens. J Cataract Refract Surg, 2011. 37(4): p. 763-6.
93. Rikimaru, T., et al., Efficacy of common antiseptics against multidrug-resistant Mycobacterium
tuberculosis. Int J Tuberc Lung Dis, 2002. 6(9): p. 763-70.
94. Shimada, H., et al., Reduction of anterior chamber contamination rate after cataract surgery by
intraoperative surface irrigation with 0.25% povidone-iodine. Am J Ophthalmol, 2011. 151(1): p.
11-17 e1.
95. Kim, K.H., et al., Intraocular Pharmacokinetics of Povidone-Iodine and Its Effects on Experimental

t
Staphylococcus epidermidis Endophthalmitis. Invest Ophthalmol Vis Sci, 2015. 56(11): p. 6694-

ip
700.
96. Speaker, M.G. and J.A. Menikoff, Prophylaxis of endophthalmitis with topical povidone-iodine.
Ophthalmology, 1991. 98(12): p. 1769-75.

cr
97. Halachmi-Eyal, O., et al., Preoperative topical moxifloxacin 0.5% and povidone-iodine 5.0%
versus povidone-iodine 5.0% alone to reduce bacterial colonization in the conjunctival sac. J
Cataract Refract Surg, 2009. 35(12): p. 2109-14.

us
98. Speaker, M.G., et al., Role of external bacterial flora in the pathogenesis of acute postoperative
endophthalmitis. Ophthalmology, 1991. 98(5): p. 639-49; discussion 650.
99. Shimada, H., et al., Reduced anterior chamber contamination by frequent surface irrigation with
an
diluted iodine solutions during cataract surgery. Acta Ophthalmol, 2017. 95(5): p. e373-e378.
100. Fox OJ, B.S., Chong CW, Wang SB, Wehrhahn MC, Irvine S, Francis IC, Anterior Chamber Culture
at the Conclusion of Cataract Surgery and Its Relation to Post-Cataract Surgery Endophthalmitis.
Open Access Journal of Science and Technology, 2018. 5.
M
101. Mistlberger, A., et al., Anterior chamber contamination during cataract surgery with intraocular
lens implantation. J Cataract Refract Surg, 1997. 23(7): p. 1064-9.
102. Eifrig, C.W., et al., Acute-onset postoperative endophthalmitis: review of incidence and visual
outcomes (1995-2001). Ophthalmic Surg Lasers, 2002. 33(5): p. 373-8.
ed

Table 1. Pathogens causing postoperative endophthalmitis in different countries, reused with

permission from reference [27]
pt
ce
Ac

Information Classification: General

 Pathogens causing postoperative endophthalmitis in different countries

Pathogenes Lundstro Frilin Mollan Pijl(21) Han( Cheng( Anand( Kunimot Sheng(

t
: m(11) g(7) (20) 22) 23) 24) o(25) 26)

ip
Netherla USA Taiwa India
Sweden Swede UK nds n India China
n

cr
Gram- 44% 37.6% 53% 74%
positive

us
organisms

Staphyloco 35%
cci
an
Staphylococ 5% 12% 10% 24% 8% 12%
cus aureus
M

Coagulase- 26% 62% 54% 70% 3% 13% 33% 46%

negative
Staphylococ
ed

cus (CoNS)

Enterococci 30% 31% 3% 2% 2% 12% 2% 7%

pt

Other 13.5% 6% 3% 5% 3% 3% 11% 3%

Gram-
positive
ce

organisms

Streptococc 7% 20% 19% 9% 3% 4% 10% 6%

Ac

Gram- 12.5% 14% 7% 6% 6% 56% 41.7% 26% 13%

negative
organisms

(Pseudomo
nas sp.,
Enterobact

Information Classification: General

 eria sp.)

Negative 16.5% 13%

cultures

Fungi - 21.8% 17% 13%

Actinomyce 4%
tes-related

t
organisms

ip
cr
us
an
M
ed
pt
ce
Ac

Information Classification: General