ESCRS Endophthalmitis
ESCRS Endophthalmitis
ESCRS Endophthalmitis
Peter Barry
Luis Cordovs
Susanne Gardner
These guidelines are dedicated to Per Montan and colleagues at St Eriks Eye Hospital, Stockholm, Sweden.
They are the unsung heroes of intracameral antibiotic prophylaxis of endophthalmitis following cataract surgery.
Published by the European Society of Cataract and Refractive Surgeons, Temple House, Temple Road, Blackrock, Co Dublin, Ireland www.escrs.org
TABLE OF CONTENTS
1. INTRODUCTION
2.
DEFINITION OF ENDOPHTHALMITIS
3.
4.
MICROBIAL SPECTRUM OF POSTOPERATIVE ENDOPHTHALMITIS
Common sources of infection in postoperative endophthalmitis
Commonly isolated microbial species in postoperative endophthalmitis
Microbial spectrum of endophthalmitis in the ESCRS study
Microbial spectrum of endophthalmitis: recent reports
Methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE),
and increasing resistance to common topical antibiotics
2
2
3
3
4
5
5.
8
8
6.
10
7.
10
8.
13
9.
15
10.
PREOPERATIVE ANTISEPSIS
16
11.
OPERATING THEATRE
17
12.
18
Diagnosis 18
Microbiology testing
19
PCR
20
TASS vs Infectious endophthalmitis
20
Treatment of acute postoperative endophthalmitis
21
Chronic saccular endophthalmitis
24
13.
INTRAVITREAL ANTIBIOTICS
26
14.
27
15.
28
Allergy to cefuroxime
Choice of postoperative drop regimen
Choice of intracameral injection, subconjunctival injection or topical drops
28
29
30
31
33
39
1 INTRODUCTION
Endophthalmitis is a serious complication of cataract
surgery that every ophthalmic surgeon - and patient strives to avoid. The visual loss and debilitation that occur
in a large proportion of postoperative endophthalmitis
cases can be severe and irreversible. Those most in need
of the operation are often those at greatest risk, such as
the elderly. Without knowing exactly how, when or why to
intervene with effective prophylactic measures, virtually
every surgeon today follows a standard of care that involves
antisepsis and antibiotics.
Although cataract surgery ranks among the most frequently
performed surgical procedures worldwide, data to define
the most effective prophylactic measures have been nearly
impossible to generate, given the large patient numbers
needed to conduct clinical trials. Prevention and elimination
of postoperative endophthalmitis, however, is a constant
goal of every ophthalmic surgeon.
The clinical practice of administering a direct intracameral
injection of cefuroxime at the close of cataract surgery
to reduce endophthalmitis rates was first implemented
by a group of Swedish surgeons, to whom this edition
of the Guidelines is dedicated. The clinical benefit of
this intervention seemed apparent. In order to test the
hypothesis in a scientific manner, the European Society
of Cataract and Refractive Surgeons mounted a large
randomized clinical trial to evaluate the intracameral
DEFINITION OF ENDOPHTHALMITIS
MICROBIAL SPECTRUM OF
ENDOPHTHALMITIS IN THE ESCRS STUDY
The microorganisms identified in the four ESCRS study
groups appear in Table 3. In keeping with most reports,
Gram-positive microbes predominated, including species
of coagulase-negative staphylococci (CNS), streptococci,
and also other staphylococci. Particularly in Group A, the
group without intracameral cefuroxime (that received only
standard preoperative povidone-iodine, and postoperative
Group B
2 Streptococcus pneumoniae
1 Streptococcus salivarius
1 Streptococcus suis
1 Streptococcus mitis, Staphylococcus epidermidis
1 Staphylococcis auereus, Staphylococcus epidermidis,
Propionibacterium acnes
3 Staphylococcus epidermidis
1 Propionibacterium acnes
2 Staphylococcus epidermidis
Group C
Group D
1 Streptococcus salivarius
1 Streptococcus sanguinis
1 Streptococcus oralis
1 Staphylococcus aureus
2 Staphylococcus epidermidis
1 Staphylococcus hominis/haemolyticus
1 Staphylococcus warneri
* One drop 1 hour before surgery, 1 drop half an hour before surgery, 1 drop immediately postoperation, 1 drop 5 minutes later, and 1 drop 5 minutes
later again. All groups received povidone-iodine 5% (Betadine) before surgery and were presented levofloxacin 0.5% eyedrops from days 1 to 6 after
surgery 4 times daily.
MICROBIAL SPECTRUM OF
ENDOPHTHALMITIS: RECENT REPORTS
(n) (%)
Enterococci
42 31%
CNS
35 26%
Other streptococci
7%
Other gram-positive
6%
Pseudomonas species
10
7%
Enterobacteria species
5%
Other gram-negative
1%
1%
No growth
17
13%
2%
135 100%
MICROBIAL SPECTRUM OF
ENDOPHTHALMITIS IN VARIOUS REGIONS
The microbiologic spectrum of post-cataract
endophthalmitis has wide geographical variations as seen
in the series depicted in Table 6. In countries such as India
and China, the percentage of Gram-negative and fungal
UK2 NETHERLANDS3
GRAM-POSITIVE
93.4
INDIA5
CHINA6
53.1
73.9
CNS
70 62.3
S. AUREUS
10
4.9
12
11.4
12.4
STREPTOCOCCUS SPP.
19.6
19
2.9
6.2
ENTEROCOCCUS SPP.
3.3
1.8
1.4
7.2
OTHER GRAM-POSITIVE
3.3
5.2
10
2.6
GRAM-NEGATIVE
6.6
42
13.4
FUNGAL
53.6
INDIA4
26.2
Note that polymicrobial cultures occurred and are not separately identified.
1 Adapted from Han et al. 1996.
2 Adapted fro, Mollan et al. 2007.
3 Adapted from Pijl et al. 2010.
4 Adapted from Jambulingam et al. 2010.
5 Adapted from Kunimoto et al. 1999. Gram-positive includes 46.8% cocci and 6.3% bacilli.
CNS specified as S. epidermidis. Ps. aeruginosa accounted for 19.8% of Gram-negative microbes.
6 Adapted from Sheng et al. 2011.
METHICILLIN-RESISTANT S. AUREUS
(MRSA) AND S. EPIDERMIDIS (MRSE), AND
INCREASING RESISTANCE TO COMMON
TOPICAL ANTIBIOTICS
The issue of potential infection by MRSA and MRSE is
gaining attention as more of these resistant strains appear
in endophthalmitis isolates from around the world. In
2010, Major and associates from the Bascom Palmer Eye
Institute, USA, reported that MRSA was recovered in 41%
of 32 cases of endophthalmitis caused by Staphylococcus
aureus (after various ocular surgeries) in a retrospective
series dated January 1, 1995 through January 1, 2008.
Of interest, MRSA isolates showed a 62% resistance rate
to the fourth generation fluoroquinolones moxifloxacin
and gatifloxacin [per Fig. 1, Major et al, AJO 2010]. In
this series, as in the Ocular TRUST report, MRSA were
highly susceptible to trimethoprim, but poorly susceptible
to fluoroquinolones and other agents. In Ocular TRUST,
only 15.2% of MRSA isolates were susceptible to the
fluoroquinolones tested.
Figure 1.
REFERENCE
(number of patients)
0.048 0.35a
0.05
0.35
9 countriesb
0.044 (2289)c
0.08 (3971)d
0.55 (4219)d
0.014e 0.31f
South Africa
United States
0.043 (7057)g
0.39i
REFERENCE
(number of patients)
Singapore
Spain
0.422 (5930)
Spain
a From July 1999-June 2006, subconjunctival cefazolin and other agents were given at end of surgery.
From July 2006 to June 30, 2010, cefazolin was changed to intracameral injection.
b From January 1996-December 2002, no intracameral cefazolin was administered.
From January 2003-December 2009, patients received intracameral cefazolin 1mg cefazolin at the end of surgery.
c From January 2002 - December 2003, no intracameral cefazolin was administered.
From January 2004-December 2007, patients received intracameral cefazolin 2.5mg at the end of surgery.
HISTORICAL BACKGROUND
ENDOPHTHALMITIS RATES
Reported background postoperative endophthalmitis
rates have fluctuated over the past 50 years, along with
advances in surgical techniques, such as ICCE without
suture, to ICCE with suture, ECCE with IOL and sutures,
phacoemulsification, initially with incision enlargement to
accommodate rigid IOL, then phacoemulsification with
small incision IOL, among other factors. Utilisation of, and
improvements in, surgical microscopes also contributed
substantially to the overall quality of the surgical procedure.
Early in the 20th century, the incidence of endophthalmitis
after cataract surgery was fairly high - approximately 10%.
The advent of ECCE (extracapsular cataract extraction)
using a scleral or limbal incision, along with improved
hygiene, reduced this infection rate (c. 1970-1990) to
approximately 0.12% in Europe and 0.072% in the United
States. For the decade between 1990 - 2000, reported
endophthalmitis rates varied greatly, actually increasing
after the introduction of phacoemulsification and clear
cornea incisions (CCI), with some retrospective studies
reporting rates between 0.3 - 0.5%.
A degree of controversy has arisen in recent years over
endophthalmitis rates in U.S. surgical centres that claimed
rates already as low as those achieved in European
countries that use an intracameral injection, presumably
because of their more aggressive use of perioperative
antibiotic drops in lieu of intracameral injection. These
0.31%
2007-2009
Excluding allergy/PCR
0.143% 2.2x
2010-2011
All patients
0.014% 10.2x
10
11
Group B
Intent to Treat
Number of patients 4054
Intent to Treat
Number of patients 4056
Per Protocol
Number of patients 3990
Per Protocol
Number of patients 3997
Group C
Group D
Intent to Treat
Number of patients 4049
Intent to Treat
Number of patients 4052
Per Protocol
Number of patients 3984
Per Protocol
Number of patients 4000
12
CASES
1 - 3
Proven Unproven
8
1
Total
9
4 - 7
8 - 14
> 14
CEFUROXIME
13
14
A) CLEAR CORNEA
INCISION AND
POSTOPERATIVE
ENDOPHTHALMITIS
The clear cornea incision (CCI)
technique is historically thought to have contributed
to an increased incidence of endophthalmtis after
phacoemulsification surgery, due to postoperative changes
in IOP that may create suction and subsequent inflow of
extraocular fluid and particles into the anterior chamber.
In a large meta-analysis, Taban and associates [Taban
2005] identified CCI in phacoemulsification as a risk factor
during the time period 1992 - 2003 where increased
endophthalmitis rates of 0.189% were seen, as compared
with rates of 0.074% observed after scleral tunnel incisions.
This risk factor (CCI) was assessed prospectively in the
ESCRS study, with similar results. Patients receiving
the CCI procedure were found 5.88 times more likely to
contract endophthalmitis than patients undergoing the
scleral tunnel technique. These results must be viewed with
caution, however, because only two of the participating 24
centres used scleral tunnel incisions routinely, with none of
the others using it more than occasionally
One important factor appears to be construction of the
tunnel. With a CSI (corneo-scleral incision], the tunnel is
more quadratic, whereas with CCI the proportions are often
double in width compared to radius, and thus more prone
to gaping. Therefore, the increased risk associated with CCI
may be reduced by suturing the corneal incision [Masket
2005]. However, recent experimental work challenges this
belief, noting that a well-constructed unsutured stepped
incision allows for less inflow than a sutured one [May 2013]
but, again, the quality of the suturing could also come into
question.
In a 2006 extensive review, Lndstrom stated there is no
conclusive evidence of the relationship between clear
corneal incision and endophthalmitis [Lndstrom 2006].
Data from the Swedish National Cataract Register that
included 225 471 cataract extractions between January
2002 and December 2004, showed only a trend for a
higher risk of endophthalmitis with CCI5. A more recent
C) SURGICAL COMPLICATIONS
As in other studies, surgical complications were associated
with a higher rate of postoperative endophthalmitis in
the ESCRS study, where the risk was increased 4.95 fold
when surgical complications occurred. While these may
be difficult to quantitate, the recent Swedish report3 found
that communication with the vitreous was a risk factor
associated with a 3.65 fold increase in postoperative
endophthalmitis rates.
In earlier reports, intra-operative capsular defect with
vitreous loss was associated with a 14-17 fold increase in
risk for endophthalmitis [Menikoff 1991, Wallin 2005].
15
10 PREOPERATIVE ANTISEPSIS
A) POVIDONE-IODINE (PVI)
16
11 OPERATING THEATRE
17
A) DIAGNOSIS
Postoperative endophthalmitis is conventionally
characterized as either acute, occurring within 6 weeks of
cataract surgery or chronic, occurring after that period of
time.
The majority of patients with acute postoperative
endophthalmitis present within 1-2 weeks after surgery,
with signs and symptoms of rapidly progressive
intraocular inflammation. Time to presentation and clinical
characteristics, according to the EVS10 and ESCRS1 studies,
are described in Tables 16 and 17, respectively.
Two recent large series of acute endophthalmitis cases
after cataract surgery describe substantially different
mean times to presentation - 5 days [Pijl 2010] vs 13 days
[Lalwani 2008] - with the latter possibly reflecting an altered
mechanism of onset associated with clear cornea surgery.
In the ESCRS Endophthalmitis study, proven
endophthalmitis cases presented within a shorter period
of time and most occurred in the study groups that did not
receive cefuroxime; in the EVS study, 50% of cases due to
other (other than CNS) Gram-positive and Gram-negative
microbes appeared within the first two postoperative days.
Pain, swollen eyelids and media haze were associated
with proven cases in the ESCRS study. In the EVS study,
where retinal vessels could be seen at presentation,
two-thirds of cases showed equivocal or no growth and
no Gram-negative microbes were found on culture. EVS
study eyes presenting with VA of light perception only,
corneal-wound abnormalities and loss of red reflex were
more likely to harbor Gram-negative or other Gram-positive
microorganisms [Wisniewski 2000].
Acute infectious postoperative endophthalmitis is initially
a clinical diagnosis, considered presumed until proven by
positive gram stain, culture or PCR. If a patient presents
with sudden decrease in visual acuity early after cataract
surgery, often with pain and signs of diffuse intraocular
inflammation (vitreous infiltration, hypopyon, red eye),
infectious endophthalmitis should be suspected (see
Section D - TASS versus infective endophthalmitis). B-scan
18
TASS
EVS
ESCRS
1-3
24% 31%
4-7
37% 31%
8-14
17% 24%
>14
22% 14%
EVS ESCRS
BLURRED VISION
94 %
92.9%
PAIN
74 %
79%
SWOLLEN EYELIDS
34 %
46.25%
HYPOPYON
75-85 %*
72%
RED EYE
82 %
**
MEDIA HAZE
79 %
63%
Microbiology, Cultures
Ideally, samples should be plated directly onto culture
media but, if not possible, blood culture bottles (particularly
paediatric ones) offer a useful option [Joondeph 1989,
Kratz 2006]. In the EVS study, two solid media (chocolate
agar and saboraud dextrose agar) and a broth (enriched
thioglycollate) were used. Strict criteria defined a
confirmed positive culture (CPC) and a laboratory
confirmed infection (LCI), giving an overall positivity rate
of 69%, with undiluted vitreous the best sample source
(Tables 18 and 19). Similar culture media were used in
the ESCRS study, with a positivity rate of 48%, which
increased to 69% when PCR was taken into account. Note
that cultures must be retained for at least 15 days to detect
any slow growing microorganisms. Antibiotic susceptibility
testing (requiring 24-48 hours time) can be performed with
isolates from the initial cultures, or directly using the RAST
method [Mio de Kaspar 2002] (requiring 6-10 hours).
B) MICROBIOLOGY TESTING
Aqueous and vitreous samples are delivered to the
forewarned microbiologists for Gram-stain culture and
microbial sensitivity testing, with instructions to deepfreeze a sample for polymerase chain reaction (PCR) if
not available on-site. Samples may be sent in the original
syringe or in sterile Eppendorf tubes. If the Gram stain
and culture are negative after 24 to 48 hours, the sample
reserved for PCR analysis can be dispatched to the relevant
laboratory.
Gram Stain
Stains, Gram for bacteria and others such as calcofluor
when fungi or other pathogens are suspected, are useful
because they can offer immediate confirmation of the
infectious nature of this postoperative inflammation. In
the EVS study, Gram stain was positive in 43% of vitreous
samples and in19% of aqueous samples; in the ESCRS
study, Gram stain detected 5 out of 8 streptococcal
infections.
19
C) PCR
PCR, with broad range primers targeting highly conserved
regions of eubacterial 16S rDNA (18S rDNA for fungi), can
detect and amplify minute amounts of bacterial DNA that
are subsequently sequenced and identified. It offers much
improved pathogen detection, especially in the case of
chronic endophthalmitis with low pathogen counts [Hykin
1994, Lohmann 1998]. In the ESCRS study, PCR tests
were carried out centrally and replicated independently at
two centers, yielding 6 additional positive cases that were
negative by Gram stain or culture.
However, the increased risk of contamination due to the
high sensitivity of the method, along with the absence of
antibiotic sensitivity testing and the partial lack of quality
control standards in routine diagnostic laboratories, have
limited its routine use thus far.
Some centres have direct access to PCR; alternatively,
samples can be deep frozen for identity of the
microorganism at a future time (i.e. if the cultures are
negative but an infectious origin is suspected). In this case,
samples can be sent for PCR analysis at a later date. One
drop of aqueous humor and one drop of vitreous humor
20
21
22
Preparation Guide
An antibiotic combination is injected separately intravitreally
and repeated as necessary, according to clinical response,
at intervals of 48 to 72 hours depending on the degree of
drug retention after injection. In most cases intravitreal
antibiotics need to be administered only once to control the
infection (7% of EVS patients received a repeat intravitreal
antibiotic injection between 36-60 hours). Repeated
injections are reported to increase the retinal toxicity of
intravitreal antibiotics [Oum 1992].
Intravitreal antibiotic doses must be highly accurate
because the margin for error between chemotherapy
and toxicity is narrow, especially for aminoglycosides
(gentamicin, 200 g is effective but 400 g may be
toxic, causing macular infarction). Since initial therapy
should cover both Gram-positive and Gram-negative
microorganisms, the most common antibiotic combinations
are as follows:
First choice: vancomycin (1mg) plus ceftazidime (2mg)
Second choice: vancomycin (1mg) plus amikacin (0.4mg),
specifically in -lactam sensitive patients (see discussion
on allergy under prophylaxis and Section 15 of these
Guidelines). Despite the synergy between vancomycin and
amikacin for Gram-positive microbes, many surgeons are
abandoning the use of aminoglycosides for treating Gramnegative bacteria because of the risk of retinal toxicity.
Antibiotics that have been used relatively safely for
intravitreal injection are shown in Table 20 opposite. The
Table lists non-toxic doses of antibiotics; however, consider
reducing the dose (some would suggest by 50%) if a full
vitrectomy has been performed, since the vitreous would
have prevented rapid diffusion of antibiotics towards the
retina. In addition, silicone oil and gas-filled eyes require a
substantial dose reduction (1/4-1/10 of the standard dose
has been suggested) taking into account the reduced fluid
distribution volume that remains in the eye [Hegazy 1999].
The antibiotics for intravitreal injection should be supplied,
freshly diluted, by the hospital pharmacy department.
However, for emergency cases, a method for diluting the
drugs in the operating theatre is provided in Appendix I.
Due to potential antibiotic physical or chemical
incompatibility issues, it is important to use separate
syringes and needles for each drug to be injected
(antibiotics and steroid) and not mix the drugs together in
the same syringe. Most incompatibilities are physical in
nature - that is, they produce a precipitate (as opposed to
invisible chemical inactivation or degradation) - and the
more concentrated the solutions, the more likely they are to
produce a precipitate when mixed.
Up to 0.1 ml of solution for injection can be lost in the
hub of the syringe and needle when drugs are diluted or
prepared for injection into the eye.
Always draw up a sufficient volume of drug to fill about half
a 1 ml syringe (e.g. 0.4 0.5 ml). Then place the needle you
will use to inject into the vitreous (30G) onto the syringe.
Take care not to leave any air in the syringe and needle
In this way, the surgeon will inject only what is in the syringe
and will not need to look continuously at the barrel to
assure that only the needed 0.1 ml is injected.
Dexamethasone (preservative-free) is often given by
intravitreal injection (dose = 400 g in 0.1ml volume,
using the commercial preparation containing 4 mg/ml) but
should not be mixed with antibiotics in the same syringe. It
produces, accompanied with antimicrobial therapy, a more
rapid reduction of intraocular inflammation; however, there
is conflicting evidence about its effect on visual outcome,
as results from several studies report a range of results from
negative effect [Shah 2000] to no effect [Das 1999] to a
beneficial effect [Gan 2005, Albrecht 2011].
Duration (h)**
Amikacin
400
24-48
24
Ampicillin
2000 (2 mg)
24
Amphotericin
5 or 10
24-48
6.915.1
Cefazolin
2000 (2 mg)
16
Ceftazidime
2000 (2 mg)
16-24
16
Cefuroxime
2000 (2 mg)
16-24
Clindamycin
1000 (1 mg)
16-24
Erythromycin
500
24
Gentamicin
200
48
12-35
Methicillin
2000 (2 mg)
16-24
3-5
Miconazole
5 or 10
24-48
Moxifloxacin
50-160
Oxacillin
500
24
Vancomycin
1000 (1 mg)
48-72
Voriconazole
100
1.72
30
2.5
Adapted from selected references including Peyman GA, Lad EM, Moshfeghi DM. Intravitreal injection of therapeutic agents.
Retina 2009; 29: 875-912. **
Duration of meaningful levels as described in literature reports.
23
24
IOAB
12/12 1/2 13/14
93%
PPV
5/10 5/10 10/20
50%
PPV + PC
2/14
4/9
6/23
26%
PPV + TC + 0/12 0/13 0/25
IOLx 0%
Adapted from Deramo et al. 2001.
25
13 INTRAVITREAL ANTIBIOTICS
26
27
Figure 4A, 4B
A) ALLERGY TO CEFUROXIME
The prevalence of penicillin allergy has been variously
estimated, but these estimates often included patient
reporting that may overstate both the nature and incidence
of a true allergic reaction. The incidence of true penicillin
allergy, as confirmed by skin testing, in patients claiming
a penicillin allergy is only about 10-20% [Salkind 2001].
Some allergic manifestations may be mild, but a severe,
true allergy to penicillin involves IgE-mediated immunologic
responses that may lead to anaphylaxis. The incidence of
penicillin anaphylaxis is estimated at 0.015-0.004% [Idsoe
1968].
However, there is interest in the cross-reactivity between
penicillins and cephalosporins, and specifically, the risk
of potential cross-allergenicity with cefuroxime. The true
cross-allergenicity between penicillins and cephalosporins
is lower than suggested in early reports, and is lower
for the second to fourth generation cephalosporins than
first generation cephalosporins. True cross-reactivity
between penicillins and cephalosporins is now linked to
the molecular configuration of the specific compounds in
28
Intracameral
Antibiotics Only
+ Preop Topical
Antibiotics*
Cases/total
98/396,894
8/47,574
Percentage 0.025% 0.017%
+Postop Topical
+ Preop and Postop
Antibiotics Antibiotics
2/10,382
3/7,307
0.019% 0.041%||
Included chloramphenicol before and after the procedure or chloramphenicol before and fusidic acid after the procedure
Moxifloxacin vs Cefuroxime
Choice of intracameral antibiotic: cefuroxime or
fluoroquinolone?
The literature (Espiritu 2007), (Arbisser 2008), (Lane
2008) describes use of intracameral fluoroquinolone (FQ)
(moxifloxacin in particular), in lieu of cefuroxime, citing
a broader spectrum of activity especially against Gramnegative bacteria, and the risk of cephalosporin allergy.
The issue of cephalosporin allergy has been addressed
above, showing that cross-allergenicity with penicillin is not
29
Spectrum of activity
The criticism has been levied that agents such as
moxifloxacin have a broader spectrum of activity than
cefuroxime, especially against Gram-negative microbes.
The incidence of MRSA/MRSE in endophthalmitis isolates,
as well as E. faecalis, is also cited.
Practically speaking, one can begin by considering
whether microorganisms outside the common spectrum
of cefuroxime, such as Gram-negative strains, especially
Ps. aeruginosa, methicillin-resistant strains, or E. faecalis
(which is described more recently) are managed by the
preoperative PVI application, whether they are likely to
be intraoperative contaminants, or likely postoperative
contaminants. The organisms causing endophthalmitis in
the post operative period may vary among regions of the
world, and the surgeon is advised to be aware of these
trends.
When administered intracamerally, only agents without
benzalkonium chloride (BAK) are candidates, because
BAK is toxic to the corneal endothelium. Therefore, the
potential efficacy of only moxifloxacin is discussed here, as
moxifloxacin for intracameral injection is reportedly adapted
from the preservative-free eye drop product. Appendix II
describes bacterial killing times for fluoroquinolone agents
with, and without, BAK. That section shows that long
exposure times may be necessary for moxifloxacin (without
BAK) to kill microbes commonly causing endophthalmitis.
Even a concentration of 5000 mcg/ml (=5 mg/ml) required
30
31
32
500mg
METHOD 2
to 10ml (NS)
50mg/ml
0.8ml
9.2ml
4mg/ml
50mg/ml
250 mg
500mg
10ml(NS)
25mg/ml
5ml (NS)/50ml bottle (see overleaf)
2ml
1ml
0.5ml
0.1ml
1ml
2ml
10mg/ml
20mg/ml
3ml
9ml
9.5ml
10mg/ml
100mcg/ml
2mg/ml
----------- [2000mcg/ml]
9ml
3ml
1000 mcg
10 mcg MICONAZOLE
5 mcg AMPHOTERICIN
Dose
Ordered
(Note: if INTRATHECAL injectable products are available, these usually do not contain preservatives, and are preferred to products that do contain preservatives.
Note that concentrations of these products may be different from products for parenteral injection.)
VANCOMYCIN
METHOD 2
MICONAZOLE 10mg/ml
ampule -1ml
1mg/ml
---------------
METHOD 2
40mg/ml
-------------
(unpreserved)
+ 9ml (NS)
2000mcg/ml
+ 1ml NS to
volume of 3ml
3000mcg/
ml minim,
use 2ml
GENTAMICIN
METHOD 1
100mg/ml
to 10ml (NS)
+1ml NS to
volume of 3ml
1 Gram
(=1000mg)
500mg
CLINDAMYCIN 300mg/2ml
METHOD 2
CEFTAZIDIME
500mg
AMIKACIN
Antibiotic
Vial size
Amount
Initial
Aliquot
Added to Final
of initial diluent,
Concentration
Volume Concentration
to/with volume
Normal Saline
33
34
Topical Drops
Prophylactic preoperative antibiotic drops are instilled in the
tear film with two basic aims: a) to reduce microbial flora
in the precorneal tear film prior to surgery, and b) to allow
diffusion of topically applied antibiotic into the anterior
chamber with the intention of combating bacteria at that
site.
Three distinct periods of time may be described in
the antibiotic prophylaxis of cataract surgery: (1) the
preoperative time period (where topical drops are intended
to reduce or eliminate bacteria on the ocular surface);
(2) the intra-operative period (where contamination may
occur during the surgical procedure itself); (3) the early
postoperative period where wound healing, surface
antisepsis and environmental factors may still induce
infection.
Figure 1A
Figure 1B
Fig. 1A: adapted from Callegan et al. Adv Ther 2009;26:447. Bacteria were
exposed in vitro to gatifloxacin 0.3% or moxifloxacin 0.5% commercially
available drops.
Fig 1B: adapted from Hyon et al. J Cat Refract Surg 2009;35:1609.
35
Large interpatient variability after drops: peak SD, range (g/ml, gm)
TEARS
levofloxacin 221.06
256.68
ciprofloxacin 11.28
norfloxacin
13.28
6.98
8.78
besiifloxacin
540
610
AQUEOUS HUMOR
Sundelin et al, 2009 levofloxacin
Koch et al. 2006
levofloxacin
4.4 2.56-7.46
1.14
0.72
0.94
1.86
0.72
1.06
1.58
0.75
moxifloxacin
36
Levofloxacin
0.5% 1.5%
4.430
Sundelin 2009
Bucci 2004
1.619
0.0523
1.31 0.63
Solomon 2005
1.18
0.48
Kim 2005
1.74
Katz 2005
Price 2005
1.26
2.28
Hariprasad 2005
1.86
McCulley 2006
2.16 0.82
Ong-Tone 2007
0.9
0.3
Holland 2008
37
38
Moxifloxacin
0-3h
4.41
Moxifloxacin
Gatifloxacin
0-2h
1.2
0.4
Holland et al.
Cornea 2008
Irrigating Solutions
Irrigating solutions deliver a flow of antibiotic at a constant
concentration. However, these antibiotic concentrations
are considerably lower than concentrations delivered
by intracameral injection; there is also no means of
quantitating the total exposure to antibiotic after irrigation.
The additional factor of time of exposure to antibiotic
also mitigates against the usefulness of these irrigating
solutions. In vitro antimicrobial activity of vancomycin is
observed after approximately 3-4 hours, with full activity
exhibited in about 24 hours [Kowalski 1998, Caillon 1989,
Gritz 1996, Keverline 2002].
39
BIBLIOGRAPHY
1.
40
Beigi, B., Westlake, W., Chang, B., Marsh, C., Jacob, J., Riordan,
T.: The effect of intracameral, per-operative antibiotics on
microbial contamination of anterior chamber aspirates during
phacoemulsification. Eye 12, 1998, 390 - 394
Behrens-Baumann, W.: Mycosis of the Eye and its Adnexa. In:
Developments in Ophthalmology 32, S. Karger AG, Basel 1999 (with a
contribution by R. Rchel)
Bispo PJ, de Melo GB, Hofling-Lima AL, Pignatari AC. Detection and
gram discrimination of bacterial pathogens from aqueous and vitreous
humor using real-time PCR assays. Invest Ophthalmol Vis Sci 2011;
52: 873 881
Bodnar Z, Clouser S, Mamalis N. Toxic anterior segment syndrome:
Update on the most common causes. J Cataract Refract Surg 2012;
38: 1902-10
Bucci FA Jr , Amico LM, Evans RE.Anitmicrobial efficacy of
prophylactic gatifloxacin 0.3% and moxifloxacin 0.5% in patients
undergoing phacoemulsification surgery. Eye Contact Lens
2008;34:39-42
Caillon, J., Juvin, M. E., Pirault, J. L., Drugeon, H. B.: Activit
bactricide de la Daptomycine (LY 146032) compare celle de la
Vancomycine et de la Teicoplanine sur les bactries gram positif.
Path Biol 37, 1989, 540 - 548
Cakir M, Imamoglu S, Cekic O, et al. An outbreak of early-onset
endophthalmitis caused by Fusarium species following cataract
surgery Curr Eye Res 2009;34:988-95
Callegan MC, Novosad BD, Ramadan RT, et al. Rate of bacterial
eradication by ophthalmic solutions of fourth-generation
fluoroquinolones. Adv Ther 2009;26:447-454.
Campagna JD, Bond MC, Schabelman E, et al. The use of
cephalosporins in penicillin-allergic patients: a literature review. J
Emerg Med 2012:45; 612-620
Campagna JD, Bond MC, Schabelman E, Hayes BD. The use of
cephalosporins in penicillin-allergic patients: a literature review. J
Emerg Med. 2012 May;42(5):612-20
Carrim ZI, Mackie G, Gallacher G, Wykes WN. The efficacy of
5% povidone-iodine for 3 minutes prior to cataract surgery. Eur J
Ophthalmol. 2009 Jul-Aug;19(4):560-4.
Centers for Disease Control. Persons with Meningitis Linked to
Epidural Steroid Injections by State. Available at:http://www.cdc.gov/
hai/outbreaks/meningitis-map.html. Accessed August 12, 2013
Center for Disease Control: Recommendations for preventing the
spread of vancomycin resistance. Morb Mort Wkly Rep 44 (RR-12),
1995, 1 - 13
Chang DF, Braga-Mele R, Mamalis N, et al. Prophylaxis of
postoperative endophthalmitis after cataract surgery; results of
the2007ASCRS member survey; the ASCRS Cataract Clinical
Committee. J Cataract Refract Surg. 2007; 33:18011805
Chang B, Knowles SR, Weber E. Immediate hypersensitivity to
moxifloxacin with tolerance to ciprofloxacin: report of three cases and
review of the literature. Ann Pharmacother 2010:44;740-5
Ciulla TA, Starr MB, Masket S. Bacterial endophthalmitis prophylaxis
for cataract surgery: an evidence-based update. Ophthalmology 109,
2002, 13 - 24
Clark WL, Kaiser PK, Flynn HW Jr et al. Treatment strategies and visual
acuity outcomes in chronic postoperative Propionibacterium acnes
endophthalmitis. Ophthalmology 1999; 106: 1665-70.
Cordoves, L., Abreu, A., Seal, D., Barry, P.: Intravitreal antibiotics: The
emergency kit. J Cataract Refract Surg 27, 2001, 971 - 972
Das T, Jalali S, Gothwal VK, Sharma S, Naduvilath TJ. Intravitreal
dexamethasone in exogenous bacterial endophthalmitis: results of a
prospective randomised study. Br J Ophthalmol 1999;83:1050 1055
Deramo VA, Lai JC, Fastenberg DM, Udell IJ. Acute endophthalmitis in
eyes treated prophylactically with gatifloxacin and moxifloxacin. Am J
Ophthalmol 2006;142: 721-5.
Deramo VA, Ting TD. Treatment of Propionobacterium acnes
endophthalmitis. Cur Opin Ophthalmol 2001;12: 225-9
Derek Y. Kunimoto, DY, Das T, Sharma S, et al. Microbiologic Spectrum
and Susceptibility of Isolates: Part I. Postoperative Endophthalmitis.
Endophthalmitis Research Group. Am J Ophthalmol 1999; 128: 240-2
41
Hall EF, Scott GR, Musch DC, Zacks DN. Adjunctive intravitreal
dexamethasone in the treatment of acute endophthalmitis following
cataract surgery. Clin Ophthalmol. 2008; 2: 139-45
Han DP, Wisniewski SR, Kelsey SF et al. Microbiologic yields and
complication rates of vitreous needle aspiration versus mechanized
vitreous biopsy in the Endophthalmitis Vitrectomy Study. Retina 1999;
19:98-102
Han DP, Wisniewski SR, Wilson LA et al. Spectrum and susceptibilities
of microbiologic isolates in the Endophthalmitis Vitrectomy Study. Am J
Ophthalmol 1996; 122: 1-17
He L, Ta CN, Hu N, et al. Prospective randomized comparison
of 1-day and 3-day application of topical 0.5% mxoifloxacin in
eliminating preoperative conjuncctival bacteria. J Ocul Pharmacol Ther
2009;25:373-8
Healy, D. P., Holland, E. J., Nordlund, M. L., Dunn, S., Chow, C.,
Lindstrom, R. L., Hardten, D., Davis, E.: Concentrations of levofloxacin,
ofloxacin and ciprofloxacin in human corneal stromal tissue and
aqueous humor after topical administration. Cornea 23, 2004, 255
263
Hegazy HM, Kivilcim M, Peyman GA et al. Evaluation of toxicity of
intravitreal ceftazidime, vancomycin, and ganciclovir in a silicone oilfilled eye. Retina. 1999; 19: 553-7.
Hellinger WC, Bacalis LP, Edelhauser HF et al; ASCRS Ad Hoc
Task Force on Cleaning and Sterilization of Intraocular Instruments.
Recommended practices for cleaning and sterilizing intraocular
surgical instruments. J Cataract Refract Surg. 2007; 33: 1095-100
Hosseini H, Ashraf MJ, Saleh M, et al. Effect of povidone-iodine
concentration and exposure time on bacteria isolated from
endophthalmitis cases. J Cataract Refract Surg. 2012;38:92-6
Hsiao CH, Chuang CC, Tan HY, et al. Methicillin-resistant
Staphylococcus aureus ocular infection: a 10-year hospital-based
study. Ophthalmology. 2012;119:522-7
Hsu HY, Lind JT, Tseng L, Miller D. Ocular flora and their antibiotic
resistance patterns in the midwest: a prospective study of patients
undergoing cataract surgery. Am J Ophthalmol. 2013;155:36-44
Hykin PG, Tobal K, McIntyre G, Matheson MM, Towler HM, Lightman
SL. The diagnosis of delayed post-operative endophthalmitis by
polymerase chain reaction of bacterial DNA in vitreous samples. J Med
Microbiol 1994;40(6):408415
Hyon JU, Eser I, OBrien TP. Kill rates of preserved and preservativefree topical 8-methoxy fluoroquinolones against various strains of
Staphylococcus. J Cat Refract Surg 2009;35:1609-1613
Idsoe O, Guthe T,Willcox RR, deWeck AL. Nature and extent of
penicillin side-reactions, with particular reference to fatalities from
anaphylactic shock. BullWorld Health Organ 1968;38:15988
Jambulingam M, Parameswaran SK, Lysa S, et al. A study on the
incidence, microbiological analysis and investigations on the source of
infection of postoperative infectious endophthalmitis in a tertiary care
ophthalmic hospital: an 8-year study. Indian J Ophthalmol 2010; 58:
297-302
Jenkins CDG, Tuft SJ, Sheraidah G, et al. Comparative intraocular
penetration of topical and injected cefuroxime. Br J Ophthalmol
1996;80:685-688
Jensen, MK, Fiscella, RG, Crandall, AS, et al. A retrospective study
of endophthalmitis rates comparing quinolone antibiotics. Am J
Ophthalmol 139, 2005, 141 148
Johnson MW, Doft BH, Kelsey SF. The Endophthalmitis Vitrectomy
Study. Relationship between clinical presentation and microbiologic
spectrum. Ophthalmology 1997; 104: 261-272
Joondeph BC, Flynn HW Jr, Miller D, Joondeph HC. A new
culture method for infectious endophthalmitis. Arch Ophthalmol
1989;107:1334-7
Karaconji T, Dubey R, Yassine Z, et al. Bacterial-sized particle ingress
promoted by suturing: is this true in the real world? J Cataract Refract
Surg 2011 Dec;37:2235-6; author reply 2236-2237
Karia N, Aylward GW. Postoperative proprionibacterium acnes
endophthalmitis. Ophthalmology 2001;108:634-5
Kaynak S, Oner FH, Koak N, Cingil G. Surgical management of
postoperative endophthalmitis: comparison of 2 techniques. J Cataract
Refract Surg 2003;29: 966-9
42
Menikoff, J A, Speaker M G, Marmor M, Raskin E M: A casecontrol study of risk factors for post-operative endophthalmitis.
Ophthalmology 98; 1991: 1761 - 1768
43
Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination.
Is this patient allergic to penicillin? An evidence-based analysis of the
likelihood of penicillin allergy. JAMA 2001:285; 2498-505
Seal, D. V., Barry, P., Gettinby, G. et al.: ESCRS study of prophylaxis
of postoperative endophthalmitis after cataract surgery: Case for a
European multi-centre study. J Cataract Refract Surg. 32, 2006, 396
406
Seal, D., Wright, P., Ficker, L., et al.: Placebo-controlled trial of fusidic
acid gel and oxytetracycline for recurrent blepharitis and rosacea. Br J
Ophthalmol 1995; 79: 42 - 45
44
Lai WW, Chu KO, Chan KP, et al. Differential aqueous and
vitreous concentrations of moxifloxacin and ofloxacin after topical
administration one hour before vitrectomy. Am J Ophthalmol.
2007;144:315-8.
McCulley JP, Caudle D, Aronowicz JD, et al. Fourth generation
fluoroquinolone penetration into the aqueous humor in humans.
Ophthalmology. 2006 Jun;113(6):955-9.
Ong-Tone L. Aqueous humor penetration of gatifloxacin and
moxifloxacin eyedrops given by different methods before cataract
surgery. J Cataract Refract Surg. 2007 Jan; 33(1):59-62.
Price MO, Quillin C, Price FW Jr. Effect of gatifloxacin ophthalmic
solution 0.3% on human corneal endothelial cell density and aqueous
humor gatifloxacin concentration. Curr Eye Res. 2005 Jul; 30(7):5637.
Raizman MB, Rubin JM, Graves Al, et al. Tear concentrations of
levofloxacin following topical administration of a single dose of 0.5%
levofloxacin ophthalmic solution in healthy volunteers. Clin Ther. 2002
Sep;24(9):1439- 50.
Solomon R, Donnenfeld ED, Perry HD, et al. Penetration of topically
applied gatifloxacin 0.3%, moxifloxacin 0.5%, and ciprofloxacin 0.3%
into the aqueous humor. Ophthalmology. 2005 Mar;112(3):466-9.