ARTICLE

Ocular toxicity after intracameral injection of very

high doses of cefuroxime during cataract surgery
Marie-No€elle Delyfer, MD, PhD, Marie-Benedicte Rougier, MD, PhD, Sandy Leoni, MD,
Qiuhua Zhang, MD, Francis Dalbon, MD, Joseph Colin, MD, Jean-François Korobelnik, MD

PURPOSE: To report cases of intraocular inflammation after intracameral injection of a very high
dose of cefuroxime at the end of uneventful cataract surgery.
SETTING: Department of Ophthalmology, Bordeaux University Hospital, Bordeaux, France.
DESIGN: Case series.
METHODS: Patients were followed on an outpatient basis and were examined postoperatively at 1
and 5 days and 6 weeks. Central macular thickness, angiography, central corneal thickness (CCT),
endothelial cell density (ECD), and electroretinography (ERG) were analyzed to evaluate ocular
toxicity.
RESULTS: One day postoperatively, the mean corrected distance visual acuity (CDVA) was 0.95 log-
MAR G 0.40 (SD). All the cases had moderate anterior inflammation. Retinal optical coherence
tomography scans systematically showed extensive macular edema (mean 843.2 G 212.7 mm)
associated with a large serous retinal detachment. Fluorescein angiograms showed diffuse leakage
without abnormal retinal perfusion. At 5 days, the mean CDVA improved significantly to 0.52 G
0.29 logMAR (P<.005), as did the macular edema and serous retinal detachment (mean 339.4 G
138.3 mm) (PZ.005). At 6 weeks, the mean CDVA reached 0.09 G 0.06 logMAR. Modifications in
CCT and ECD were similar to those observed after uneventful phacoemulsification. The macular thick-
ness (mean 288.4 G 22.6 mm) and profile returned to normal in all patients, although ERG recordings
showed reduced rod photoreceptor cell function (P<.05).
CONCLUSIONS: Intracameral injection of high doses of cefuroxime induced anterior and posterior
inflammation. Without surgical intervention, the final visual outcome was satisfactory in all cases.
Long-term retinal function, however, must be assessed through repeated ERG recordings.
Financial Disclosure: No author has a financial or proprietary interest in any material or method
mentioned.
J Cataract Refract Surg 2011; 37:271–278 Q 2011 ASCRS and ESCRS

Cataract extraction is the most commonly performed
surgical procedure in elderly people in industrialized
countries.1 With the rise of life expectancy, cataract
surgical needs will keep increasing, as will the healthy
aging population’s expectations of significant
improvements in postoperative visual acuity.
Bacterial endophthalmitis, although rare, is among
the most feared and devastating postoperative compli-
cations because it can lead to severe and permanent
visual loss.2 Prevention of postoperative endophthal-
mitis thus represents one of the main challenges facing
cataract surgeons. In addition to recommendations to
use povidone–iodine preoperatively,3,4 avoid silicone
intraocular lenses (IOLs),5 and carefully consider the
incision type and location,5–7 the administration of
prophylactic antibiotic agents has kept the rate of post-
operative endophthalmitis at its lowest level.7,8 Of the
different antibiotic strategies, the intracameral injection
of cefuroxime (0.1 mL of 10.0 mg/mL solution) has been
shown to induce a 5-fold reduction in the incidence of
postoperative endophthalmitis, a result that is signifi-
cantly better than with perioperative instillation of
topical levofloxacin eyedrops.1,5,9 Cefuroxime is a sec-
ond-generation bactericidal cephalosporin with an an-
tibacterial spectrum well suited to bacteria implicated
in postoperative endophthalmitis.8 Unlike vancomy-
cin, it is not a last-resort antibiotic agent that must be
reserved for treatment and not prophylaxis, as recom-
mended by the U.S. Centers for Disease Control and
Prevention, Atlanta, Georgia.8,10 Because cefuroxime

Q 2011 ASCRS and ESCRS 0886-3350/$ - see front matter 271

Published by Elsevier Inc. doi:10.1016/j.jcrs.2010.08.047
272 OCULAR TOXICITY OF CEFUROXIME
is a time-dependent kill agent, it has been debated
whether the choice of a concentration-dependent kill
antibiotic, such as moxifloxacin, would be more appro-
priate.11 However, to this day, intracameral cefuroxime
remains the most cost-effective way to prevent postop-
erative endophthalmitis.12 At the recommended dose
of 1.0 mg in 0.1 mL, cefuroxime presents no ocular
toxicity and is well tolerated.13–16 Intracameral injection
of cefuroxime has therefore been proposed as “a
standard part of the procedure of modern phacoemulsi-
fication cataract surgery.”9
However, no ready-to-use ocular formulations of ce-
furoxime are available. The 10.0 mg/mL solution is
prepared in hospital pharmacies and stored at 4 C
for a limited time or reconstituted by the surgeon in
the operating room, which risks mistakes during the
2 steps of dilution. Minor dilution errors have occurred
in the past without incidence.17 Here, however, we
report 6 cases of intraocular inflammation after intra-
cameral injection of a very high dose of cefuroxime
secondary to misunderstanding of the dilution proto-
col at the end of uneventful cataract surgery.
PATIENTS AND METHODS
This series comprises cases of phacoemulsification cataract
surgery performed on January 20, 2010. No perioperative
complications were recorded. All patients received a single-
piece AcrySof Natural SN60AT yellow-tinted IOL (Alcon
Laboratories, Inc.). It was the first time the eye surgeon
used cefuroxime.
The surgeon reconstituted the cefuroxime in the operation
ward by adding 7.5 mL of a balanced salt solution to
a 750.0 mg vial of lyophilized antibiotic powder. The
100.0 mg/mL solution was not rediluted, and a volume
containing between 0.4 mL and 0.5 mL was intracamerally
injected at the end of the surgical procedure, resulting in an
injection of 40.0 to 50.0 mg of cefuroxime instead of the recom-
mended dose of 1.0 mg. The mistake was based on the
surgeon’s misunderstanding of the dilution protocol resulting
from inattentive study of the literature. The day after surgery,
all patients had poor vision and ocular inflammation. They
were referred to our department.
Patients were examined postoperatively at 1 and 5 days
and 6 weeks. No surgical procedure (anterior chamber wash-
out or vitrectomy) was performed. At each clinical evalua-
tion, corrected distance visual acuity (CDVA), slitlamp
Submitted: July 11, 2010.
Final revision submitted: August 25, 2010.
Accepted: August 26, 2010.
From the Department of Ophthalmology, Bordeaux University
Hospital, Bordeaux, France.
Corresponding author: Marie-No€elle Delyfer, MD, PhD, Department
of Ophthalmology, Bordeaux University Hospital, Place Amelie
Raba-Leon, 33076 Bordeaux Cedex, France. E-mail: marie-noelle.
delyfer@chu-bordeaux.fr.
J CATARACT REFRACT SURG - VOL 37, FEBRUARY 2011
biomicroscopic examination, intraocular pressure (IOP) mea-
surement, and indirect ophthalmoscopy were performed.
Fundus autofluorescence imaging, central macular thickness
(CMT), and a retinal optical coherence tomography (OCT)
profile were assessed by spectral-domain scanning laser
ophthalmoscopy OCT (Spectralis Heidelberg Retinal Angio-
graph/OCT, Heidelberg Engineering GmbH). The OCT
mapping software automatically calculated the CMT. Fluo-
rescein angiography was performed 1 day postoperatively.
Indocyanine green (ICG) angiography was performed in
the initial case with a digital retinal camera (Topcon TRC-
50IX, Topcon Corp.). Corneal endothelial cell counts
(ECCs), expressed as cells/mm2, were taken at 1 day and 6
weeks with a noncontact specular microscope (Noncon
Robo, Konan Medical). Anterior segment OCTs (Visante
OCT, Carl Zeiss Meditec AG) were performed at 1 day and
6 weeks. The International Society for Clinical Electrophysiol-
ogy of Vision (ISCEV) standard full-field electroretinograms
(ERGs) were recorded 6 weeks postoperatively according to
standard protocols (Metrovision).18
Statistical analyses were performed using the Student
t test. A P value less than 0.05 was considered statistically
significant.
RESULTS
This case series comprised 6 patients. The mean age of
the 4 women and 2 men was 76 years (range 69 to
84 years).
Visual Acuity and Symptoms
Table 1 shows the details of each case. The mean
CDVA was 0.33 logMAR G 0.15 (SD) preoperatively
and 0.95 G 0.40 logMAR 1 day postoperatively. By
5 days postoperatively, the mean CDVA had
improved to 0.52 G 0.29 logMAR (P!.005). At
6 weeks, the CDVA reached 0.09 G 0.06. Patient 5
was the only one to report persistent halo. The im-
provement in CDVA from preoperatively to postoper-
atively was statistically significant (P!.05).
Anterior Segment Inflammation and Corneal
Changes
One day postoperatively, all the patients had moder-
ate anterior inflammation with fibrin formation (Table
1 and Figure 1), 2 patients (5 and 6) had corneal edema,
and 2 others (1 and 2) had elevated IOP. All patients
were prescribed topical tobramycin 0.3%, dexametha-
sone 0.1%, and ketorolac tromethamine 0.5% eyedrops.
Patients with elevated IOP were also given oral acet-
azolamide and topical apraclonidine 0.5%. At 5 days,
no anterior inflammation or residual high IOP was
observed. Ocular hypertension treatment was discon-
tinued in the 2 patients with transient high IOP.
The mean central corneal thickness (CCT) was
559.83 G 50.55 mm 1 day postoperatively and 530.33 G
45.60 mm at 6 weeks. The CCT at 1 day was 5.6%
 OCULAR TOXICITY OF CEFUROXIME 273

Table 1. Individual patient data over time.

Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6

Preoperative
Age (y) 74 82 70 77 84 69
Sex M M F F F F
Involved eye R R L R R R
CDVA (logMAR) 0.40 0.20 0.10 0.40 0.40 0.50
Postoperative
1 day
CDVA (logMAR) 0.70 1.60 1.00 1.00 1.00 0.40
AC cells 1C 2C 1C 2C 1C 1C
AC flare 1C 2C 0 2C 1C 2C
Vitreous haze 1C 1C !1C !1C !1C 1C
IOP (mm Hg) 34 48 20 12 12 18
CCT (mm) 503 556 594 580 626 500
ECC (/mm2) 2198 2695 2375 1980 Edema Edema
CMT (mm) 885 996 995 1008 688 487
5 days
CDVA (logMAR) 0.40 1.00 0.50 0.50 MD 0.20
CMT (mm) 304 585 277 270 MD 261
6 weeks
CDVA (logMAR) 0.10 0.10 0.05 0.05 0.20 0.05
CCT (mm) 470 509 580 574 555 494
ECC (/mm2) 2008 2114 2299 1550 1302 1751
CMT (mm) 323 285 296 272 293 266
Contralateral CMT (mm) 306 308 298 281 286 192
ERG scotopic b-wave amplitude (mV) 104.0 96.0 69.4 56.9 101.0 NI

AC Z anterior chamber; CCT Z central corneal thickness; CDVA Z corrected distance visual acuity; CMT Z central macular thickness; ECC Z endothelial cell
count; ERG Z electroretinography; IOP Z intraocular pressure; MD Z missing data; NI Z not interpretable; Pt Z patient

greater than at 6 weeks; the difference in the 2 values
was statistically significant (P!.05).
Endothelial cell counts could be measured in 4 of 6
patients 1 day postoperatively; the 2 patients in
whom the count could not be measured (5 and 6) had
corneal edema (Table 1). In the remaining patients,
the mean endothelial cell loss between 1 day and
6 weeks postoperatively was 319.25 cells/mm2. This
corresponded to a 16% decrease from the initial
ECC, although the difference was not statistically

Figure 1. Slitlamp images of patient 4 (A) and patient 6 (B) 1 day postoperatively. Patient 4 presented with postoperative inflammatory anterior
chamber fibrin formation. Patient 6 also had corneal edema.

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274 OCULAR TOXICITY OF CEFUROXIME
significant. The 2 patients in whom an ECC could not
be taken were known to have cornea guttata. At 6
weeks, the cornea guttata in patient 5 was more severe
in the operated right eye than in the contralateral left
eye. No preoperative data were available. The EEC
at 6 weeks was 1302 cells/mm2 and 1902 cells/mm2,
respectively. Patient 6 had only 1 functional eye
because the contralateral eye had several previous sur-
geries for retinal detachment, preventing comparison
between the 2 eyes once the corneal edema resolved.
Retinal Findings
No patient had previous retinal disease in the oper-
ated eye. One day postoperatively, a dilated fundus
examination showed slight vitreous haze and signifi-
cant retinal thickening in all patients. Retinal OCT scans
systematically showed extensive macular edema; the
mean CMT was 843.2 G 212.7 mm. Macular edema pre-
dominated in the outer nuclear layer and was associ-
ated with a large serous retinal detachment (Figure 2).
Fundus autofluorescence images did not yield addi-
tional differences from the contralateral eye. Patient 3
refused to have angiography after reading the consent
form. Fluorescein angiograms in the other 5 cases
showed diffuse leakage without abnormal retinal per-
fusion (Figure 3). Indocyanine green angiography was
performed only in patient 1, the first to be examined;
the angiograph showed no abnormalities (Figure 3).
By 5 days postoperatively, the macular edema and
serous retinal detachment had improved significantly
(PZ.005; data missing for patient 5); the mean CMT
was 339.4 G 138.3 mm. By 6 weeks, the profile had re-
turned to normal in all patients; the mean CMT was
288.4 G 22.6 mm. The CMT in the operated eye and
the CMT in the contralateral eye (mean 277 G 48.7 mm)
were not statistically different (PZ.47).
Electroretinographic Analysis
Electroretinographic analysis was performed in all
cases except patient 6, whose ERGs were not interpret-
able because of numerous losses of fixation and
artifacts. The ISCEV-standard full-field ERGs showed
a mean decrease in scotopic b-wave amplitude of
31.6% over the normal values provided by the manu-
facturer (85.5 G 21 mV, PZ.01), whereas photopic
b-wave amplitude remained normal, indicating alter-
ation of the rod photoreceptors. No other abnormali-
ties were seen.
DISCUSSION
The postoperative inflammation of the anterior cham-
ber that we observed in all 6 patients shared some
characteristics with toxic anterior segment syndrome
(TASS) 19 as follows: it began within 24 hours after
J CATARACT REFRACT SURG - VOL 37, FEBRUARY 2011
surgery, it was associated with fibrin formation, there
was corneal edema, and it improved with topical ste-
roid treatment. However, unlike what usually hap-
pens in TASS,19 inflammation was not restricted to
the anterior segment, which therefore argues in favor
of a diagnosis of mild toxic endophthalmitis. Only pa-
tients with elevated IOP reported ocular pain. Tran-
sient ocular hypertension in patients 1 and 2 may
have been caused by unsolved particles of cefuroxime
after reconstitution or inflammatory precipitates on
the trabecular meshwork. In TASS, corneal edema is
often linked to widespread endothelial cell damages;
corneal alterations in our cases were rather limited.
There were slight modifications in the ECC between
1 day and 6 weeks postoperatively; the modifications
were approximately the same as those observed 6
weeks after standard cataract surgery,20,21 at least in
patients 1 to 4. Our findings were not consistent with
in vitro observations by Yoeruek et al.,16 who found
an increase in endothelial cell loss with cefuroxime
concentrations higher than 2.75 mg/mL. Rapid clear-
ance of cefuroxime in the anterior chamber in vivo
may explain the discrepancies. In our last 2 patients,
preexisting cornea guttata impaired initial measure-
ments and may have represented a susceptibility fac-
tor for increased endothelial damages in the presence
of high concentrations of cefuroxime, as proposed by
€
Ozlem et al.22 However, this could not be established.
All our patients had an increase in CCT. The 5.6% in-
crease 1 day postoperatively was similar to findings
reported in the literature after uneventful phacoemul-
sification20,23 and therefore was probably not linked to
potential cefuroxime toxicity.
Retinal vulnerability to cefuroxime has been
analyzed at usual doses, and no alteration was
observed.13,15 Tolerance has been found to be good
after a 1.0 mg and a 3.0 mg intracameral injection of
cefuroxime.15,17
Anatomically, the extended macular edema and
serous retinal detachment we observed in all 6 patients
show that cefuroxime diffusion in the posterior seg-
ment was significant. Macular edema predominated
in the outer nuclear layer, implying a particular drug
susceptibility of the photoreceptors or the retinal pig-
ment epithelium (RPE), as observed in animal models
after intravitreal administration of high doses of
antibiotic agents (vancomycin24 or aminoglyco-
sides25). Fluorescein angiography showed diffuse
leakage from retinal vessels, probably as a result of dis-
ruption of the blood–retinal barrier. Because the signif-
icant inflammation of the external retina could have
been secondary to abnormal choroidal perfusion, we
performed an ICG angiogram on our first patient;
the angiogram showed no abnormalities. Postopera-
tive fundus autofluorescence images at 1 day, 5 days,
 OCULAR TOXICITY OF CEFUROXIME 275

Figure 2. Postoperative horizontal OCT scans over time. At 1 day, macular edema predominating in the outer nuclear layer was found in all
patients and was associated with an extended serous retinal detachment (asterisks). The OCT-based CMT is given for each patient and visit.
At 5 days, the macular edema and serous retinal detachment had resolved in patients 1, 3, and 6. In patient 4, a cyst persisted in the retrofoveal
area. In patient 2, although decreasing, macular edema and serous retinal detachment (asterisk) were still present. Patient 5 could not been seen at
5 days because of a pneumopathy. By 6 weeks, the macular OCT profile had returned to normal in all the patients.

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276 OCULAR TOXICITY OF CEFUROXIME

Figure 3. Fundus image (A) and angiographic findings (B to H) in patient 1. A: Blurred aspect of the fundus was observed due to anterior segment
inflammation and to slight vitreous haze. A thickening of the retina predominating at the posterior pole was noticed. The caliber of the retinal blood
vessels and the optic nerve was normal. B to E: Fluorescein angiogram images with retinal arterial phase (B), venous laminar phase (C), intermediate
phase (D, 4 mn), and late phase (E, 12 mn). Fluorescein angiography showed diffuse leakage without abnormal retinal perfusion. F to H: The ICG
angiogram with early (F, 1 mn), intermediate (G, 10 mn), and late (H, 30 mn) phases did not show choroidal perfusion abnormalities.

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 OCULAR TOXICITY OF CEFUROXIME
and 6 weeks did not show RPE alterations; that is,
there were no areas of pigment clumping or atrophy.
Functionally, initial retinal dysfunction was
assessed by the drop in visual acuity 1 day post-
operatively. However, the decrease was transient, as
evidenced by the improvement in CDVA at 5 days,
which was consistent and significant compared with
the CDVA at 1 day (P!.005). Furthermore, at 6 weeks,
the improvement in CDVA was significant compared
with the preoperative values (P!.05). Still, ERG anal-
yses at 6 weeks showed moderate alterations in rod
photoreceptor cell function, confirming a particular
drug susceptibility of the outer retina, as observed
anatomically on OCT scans and discussed above.
With the growing use of intracameral antibiotic
administration during cataract surgery, unintended
dilution errors have occurred.17,26 However, when-
ever the errors occur or are discovered, the physician
in charge must decide promptly whether additional
treatment is required for the benefit of the patient.
Should the physician opt in favor of anterior chamber
washout? Should one consider vitrectomy to limit ret-
inal damage? Such questions have to be addressed. In
this case after reviewing the pharmacokinetic data
available and the clinical characteristics of our
patients, we decided not to perform surgery. There
was no indication for anterior chamber irrigation
because intracameral cefuroxime concentration in the
aqueous humor has been shown to decrease by 4-
fold within 60 minutes after injection14; our patients
were 24 hours out from surgery and their anterior
symptoms were rather moderate. We also carefully
weighed the benefits of vitrectomy to decrease the
cefuroxime concentration in the vitreous and thus
reduce potential retinal toxicity. However, retinal tox-
icity after intravitreal injection of a high dose of antibi-
otics in animal models has been shown to be more
often related to a peak concentration of the antibiotic
agent than to the duration of tissue exposure.24,25
Therefore, we deemed the risks associated with vitrec-
tomy in an inflamed eye too high considering the rapid
ocular clearance of the drug and the absence of retinal
toxicity observed with cefuroxime in animal
experiments.13
Fortunately, the final visual outcome was relatively
satisfactory in all 6 patients, arguing against surgical
intervention in such cases. Long-term retinal function,
however, will have to be assessed through repeated
ERG recordings. With the increased use of intracam-
eral cefuroxime at the end of cataract surgery, there
is clearly a need for a self-preserved ophthalmic
formulation to avoid the important risk of dilution
error during extemporaneous compounding. Still,
the short-term stability of cefuroxime after reconstitu-
tion27 remains a limiting factor that must be overcome.
J CATARACT REFRACT SURG - VOL 37, FEBRUARY 2011
277
In the meantime, it is the surgeon’s duty to avoid dilu-
tion errors when using off-label drugs by performing
a careful and comprehensive study of the recommen-
ded protocols before using the drugs. In the case of
extemporaneous preparation in a hospital pharmacy,
multidisciplinary cooperation is essential to preclude
similar errors and control of the medication’s labels
in advance by the surgeon remains mandatory.
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