Effect of Intravitreal Triamcinolone Acetonide on Susceptibility to Experimental Bacterial Endophthalmitis and Subsequent Response to Treatment
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LABORATORY SCIENCES
Effect of Intravitreal Triamcinolone Acetonide
on Susceptibility to Experimental Bacterial
Endophthalmitis and Subsequent Response
to Treatment
Rodney S. Bucher, MD; Edward Hall, MD; David M. Reed, PhD; Julia E. Richards, PhD;
Mark W. Johnson, MD; David N. Zacks, MD, PhD
Objectives: Recent reports of high endophthalmitis rates 20 vitreous cultures were positive, whereas only 6 (30%)
after intravitreal triamcinolone acetonide injection have were positive in the 20 eyes receiving bacteria alone
raised concerns about the safety of this treatment. We (P =.001). The vitritis was significantly increased in the
sought to evaluate the effect of intravitreal triamcino- bacteria plus triamcinolone group compared with the bac-
lone injection on (1) the susceptibility to experimental teria-only group (17 of 20 vs 7 of 20 with 4⫹ vitritis, re-
bacterial endophthalmitis and (2) the subsequent thera- spectively; P =.003). In the therapeutic response study,
peutic response to antibiotic treatment. all 12 eyes developed clinical signs of endophthalmitis
within 48 hours. All vitreous samples obtained 7 days
Design: For the susceptibility study, the right eye of 40 after intravitreal vancomycin injection were culture nega-
New Zealand white rabbits received an intravitreal in- tive. However, the severity of vitritis at the time of vit-
jection of a known quantity of Staphylococcus epidermi- reous sampling was less in the eyes receiving triamcino-
dis organisms. Half of the eyes received a simultaneous lone plus bacteria compared with eyes receiving bacteria
intravitreal injection of triamcinolone acetonide, 4 mg. alone (0 of 6 vs 5 of 6 with 4⫹ vitritis, respectively; P=.02).
All eyes were examined daily for signs of endophthalmi-
tis (photophobia, conjunctival injection, and vitritis) us- Conclusions: In eyes with experimentally induced bac-
ing standardized grading protocols (scaled from 0 to 4 terial endophthalmitis, the presence of intravitreal tri-
with increasing severity). On day 7, vitreous cultures were amcinolone results in a higher culture-positive rate and
obtained. For the therapeutic response study, the right a higher degree of inflammation, suggesting an im-
eye of 12 rabbits received an intravitreal injection of S paired ocular immune response and greater susceptibil-
epidermidis organisms sensitive to vancomycin. Half of ity to infection. However, in eyes with experimentally in-
the eyes received a simultaneous intravitreal injection of duced bacterial endophthalmitis receiving early treatment
triamcinolone acetonide, 4 mg. All 12 eyes received an with intravitreal antibiotics, triamcinolone appears to sup-
intravitreal injection of vancomycin hydrochloride, 1 mg, press the ocular inflammatory response without impair-
on development of the first signs of endophthalmitis. All ing the therapeutic effect.
eyes were examined daily for 7 additional days. On day
7 after treatment, vitreous cultures were obtained. Clinical Relevance: These data suggest that caution
must be exercised when combining intravitreal triam-
Results: In the susceptibility study, all 40 eyes devel- cinolone injection with intraocular surgery.
oped signs of endophthalmitis. In eyes that received in-
travitreal bacteria plus triamcinolone, 17 (85%) of the Arch Ophthalmol. 2005;123:649-653
I
NTRAVITREAL TRIAMCINOLONE lone injection compared with other intra-
acetonide injection has been used ocular procedures.
increasingly in the treatment of Intraocular procedures, even when per-
refractory macular edema sec- formed using sterile technique, are known
ondary to a variety of retinal con- to introduce bacteria into the eye.14,15 Pre-
ditions.1-6 It has also been used in the treat- vious animal models have demonstrated
ment of subfoveal choroidal neovascular a dose-response curve for the formation
membranes.7-11 However, concerns have of culture-positive endophthalmitis after
Author Affiliations: Retina
arisen regarding the safety of this therapy, the intravitreal injection of Staphylococ-
Service, Kellogg Eye Center,
Department of Ophthalmology especially with regard to the possibility of cus epidermidis into the eye.16-20 These stud-
and Visual Sciences, University increased risk for bacterial endophthal- ies suggest that the eye can clear a lim-
of Michigan Medical School, mitis. Initial reports12,13 have suggested that ited dose of organisms, whereas an
Ann Arbor. there is a higher rate of infectious endoph- increased inoculum will result in endoph-
Financial Disclosure: None. thalmitis following intravitreal triamcino- thalmitis. A major concern regarding the
(REPRINTED) ARCH OPHTHALMOL / VOL 123, MAY 2005 WWW.ARCHOPHTHALMOL.COM
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Downloaded From: http://www.jamafacial.com/ on 02/07/2015intravitreal injection of a corticosteroid is that it might dard, sterile microbiological techniques. After incubation over-
shift the dose-response curve and thus lower the thresh- night with shaking at 37°C, the bacteria were diluted in TSB
old number of organisms required for the development and grown to an optical density reading of 0.08 to 0.10 absor-
of culture-positive endophthalmitis. bance unit as determined using absorbance at 625 nm on a spec-
trophotometer (Shimadzu UV-2401 PC; Shimadzu Scientific In-
The main goal of our study was to determine whether
struments, Columbia, Md). Serial dilutions were made in sterile
intravitreal triamcinolone increased the susceptibility for isotonic sodium chloride solution to achieve the desired bac-
culture-positive endophthalmitis in an experimental terial count per 0.1 mL. Counts were verified by plating ali-
model of bacterial endophthalmitis. In addition, we wished quots of the serially diluted samples on TSB agar (30 g/L BBL
to determine whether triamcinolone affects the thera- TSB powder, 15 g/L granulated agar [Fisher Chemicals, Fair-
peutic response to intravitreal antibiotics in eyes with ex- lawn, NJ]) and growing overnight at 37°C. An aliquot was plated
perimental bacterial endophthalmitis. both before and after the injection to ascertain that the bacte-
rial count did not change during the interval required to per-
form the injection.
METHODS For the arm of the study examining the effect of triamcino-
lone on the dose-response curve for culture-positive endoph-
All experiments were conducted in accordance with the Asso- thalmitis, the right eyes of 40 New Zealand white rabbits were
ciation for Research in Vision and Ophthalmology guidelines used. Ten rabbits were injected with a dose of 3.5 ⫻ 101 to
for the use of experimental animals, and with the approval of 4.0 ⫻ 101 organisms and 30 were injected with 3.5 ⫻ 102 to
the University Committee on the Use and Care of Animals at 4.0 ⫻ 102 organisms. In each group, half of the eyes also re-
the University of Michigan, Ann Arbor. Specific pathogen– ceived a concomitant intravitreal injection of commercially avail-
free adult male New Zealand white rabbits were used in all ex- able 40-mg/mL triamcinolone acetonide, 0.1 mL (Kenalog-40;
periments. Animals were anesthetized using a mixture of ket- Bristol-Myers Squibb Company, Princeton, NJ). In addition, in
amine hydrochloride and xylazine hydrochloride at a dose of 8 control eyes, 4 received an injection of triamcinolone ace-
40 mg/kg and 10 mg/kg, respectively. All intraocular injec- tonide, 0.1 mL, alone (to evaluate for signs of sterile endoph-
tions were given into the right eye of each rabbit and were per- thalmitis) and 4 received an injection of a higher inoculum
formed using strict sterile technique. The right eye of each rab- (3.5⫻105 to 4.0⫻105 organisms) of the same bacterial strain
bit was prepared, the lids scrubbed with a povidone-iodine to ensure the viability of the organisms. On day 7, the animals
solution, and the field covered with a sterile eye drape. Solu- were anesthetized as already described, and vitreous samples
tion containing bacteria or triamcinolone was drawn up in a of approximately 0.1 mL were obtained using a 25-gauge needle
sterile fashion into the injection syringe. A sterile lid specu- passed through the pars plana into the mid vitreous cavity un-
lum was used to maintain exposure of the injection site. All der sterile conditions. The animals were then euthanized with
injections were performed through the pars plana with the use an intracardiac injection of phenobarbital sodium. Each vitre-
of a 30-gauge needle on a 1-mL tuberculin syringe. After the ous sample was plated on TSB agar and incubated at 37°C over-
injection, a drop of 1% atropine sulfate and lubricating oint- night. After 24 hours, the plates were examined for growth.
ment was placed in the eye. All procedures were performed in For the arm of the study testing the effect of triamcinolone
the animal surgical suite of the Kellogg Eye Center vivarium on the response to intravitreal injection of vancomycin, 12 New
at the University of Michigan. After the procedure, the rabbits Zealand white rabbits were used and an inoculum of 3.5⫻103
were placed in their cages and allowed to recover using stan- to 4.0⫻103 organisms was injected. Half of the eyes (n=6) also
dard animal care protocols. received a simultaneous intravitreal injection of 40-mg/mL tri-
Rabbits were examined daily for the formation of signs of amcinolone acetonide, 0.1 mL. The eyes were examined daily
endophthalmitis. Specific features noted were photophobia, con- for signs of endophthalmitis. If endophthalmitis was detected,
junctival injection, and vitritis. Each criterion was graded on a the eye received an intravitreal injection of 10-mg/mL vanco-
scale of 0 to 4, with increasing values corresponding to increas- mycin hydrochloride, 0.1 mL, using the protocol already de-
ing severity. Vitritis was assessed with the use of indirect oph- scribed for sterile intravitreal injection. The eyes were exam-
thalmoscopy, and the grading scale was formalized as shown ined daily for 7 additional days, after which the animals were
in the following tabulation: anesthetized and the vitreous cultures obtained. Each vitreous
sample was plated on TSB agar and incubated at 37°C over-
Grade Degree of Vitritis
night. After 24 hours, the plates were examined for growth.
0 No vitritis
1⫹ Mild vitreous haze
2⫹ Moderate vitreous haze with some retina details visible RESULTS
3⫹ Good red reflex with no retina details visible
4⫹ Poor red reflex
The results for the susceptibility arm of the study are sum-
Examiners could not be masked to the status of triamcino- marized in Table 1. All 40 eyes developed signs of en-
lone injection because the triamcinolone was easily detectable dophthalmitis. Of the eyes that received intravitreal bac-
during indirect ophthalmoscopy. The use of the formal grad- teria plus triamcinolone, 17 (85%) of the 20 vitreous
ing scale, however, provided specific criteria for assigning a vi- cultures were positive. In contrast, only 6 (30%) vitre-
tritis score to each eye, thus serving to minimize any examiner ous cultures were positive in the 20 eyes receiving bac-
bias. teria alone (P =.001). In the group receiving the 102 in-
Experimental endophthalmitis was induced by injecting a oculum size, 14 (93%) of the 15 eyes that also received
known dose of vancomycin-sensitive S epidermidis (American
Type Culture Collection [ATCC] No. 12228; ATCC, Manas-
intravitreal triamcinolone were culture-positive, whereas
sas, Va) into the vitreous cavity. Organisms were washed and only 5 (33%) of the 15 bacteria-only eyes were culture-
resuspended in a total volume of 0.1 mL of sterile isotonic so- positive (P=.002). Quantitative colony counts on the vit-
dium chloride solution. Bacteria were grown in trypticase soy reous samples obtained confirmed that culture-positive
broth (TSB), 30 g BBL TSB powder per liter (Becton Dickin- eyes from the triamcinolone group had greater bacterial
son and Company, Sparks, Md), and all procedures used stan- loads than culture-positive eyes that did not receive tri-
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Downloaded From: http://www.jamafacial.com/ on 02/07/2015Table 1. Susceptibility Study Vitreous Culture Results*
Inoculum A† Inoculum B‡ Combined
(n = 10) (n = 30) (N = 40)
Culture Culture Culture
Positive Negative Positive Negative Positive Negative
With triamcinolone acetonide 3 2 14 1 17 3
Without triamcinolone 1 4 5 10 6 14
P Value§ .52 .002 .001
*Data are given as number of eyes with either positive or negative cultures.
†For A, inoculum size was equal to 3.5 ⫻ 101 to 4.0 ⫻ 101 organisms per 0.1 mL.
‡For B, inoculum size was equal to 3.5 ⫻ 102 to 4.0 ⫻ 102 organisms per 0.1 mL.
§Calculated using the Fisher exact test.
Table 2. Susceptibility Study Vitritis Score Results on Day 7*
Inoculum B‡ (n = 30) Combined (N = 40)
Vitritis Score† With Triamcinolone Acetonide Without Triamcinolone With Triamcinolone Without Triamcinolone
4⫹ 14 5 17 7
⬍4⫹ 1 10 3 13
P Value§ .002 .003
*Data are given as number of eyes with the corresponding vitritis score.
†Vitritis scores are explained in the “Methods” section.
‡For B, inoculum size was equal to 3.5 ⫻ 102 to 4.0 ⫻ 102 organisms per 0.1 mL.
§Calculated using the Fisher exact test.
amcinolone (data not shown). The group receiving the
101 inoculum size showed a similar trend toward in- With IV Triamcinolone Acetonide
Without IV Triamcinolone Acetonide
creased culture-positive eyes in the intravitreal triam- 4
cinolone group, but the difference did not reach statis-
tical significance, perhaps because of the small sample
Mean Vitritis Score
3
size.
When assessing the difference in ocular inflamma- 2
tion, there was a significant difference between the tri-
amcinolone with bacteria vs the bacteria-only eyes. Vi- 1
tritis scores were significantly higher in the 20 eyes with
triamcinolone and bacteria, with 17 (85%) having 4⫹ vi- 0
1 2 3 4 5 6 7
tritis. In the bacteria-only group, only 7 (35%) of 20 eyes
Day After Injection
had 4⫹ vitritis (P = .003) (Table 2). Of note, the onset
of vitritis in the group receiving triamcinolone ap-
Figure. Daily average vitritis scores for inoculums of 3.5 ⫻ 102 to 4.0⫻102
peared to be delayed but surpassed the severity of vitri- organisms, with or without the concomitant injection of intravitreal (IV)
tis in the bacteria-only eyes by day 5 (Figure). triamcinolone acetonide. The vitritis score on day 7 was significantly different
In the control eyes receiving triamcinolone alone, none between the 2 groups (P = .003). Vitritis scores are explained in the
“Methods” section. Limit lines indicate standard deviation.
of the 4 developed signs of sterile endophthalmitis and
all vitreous cultures were negative. In the 4 control eyes
receiving the 105 dose of organisms, all 4 had signs of
endophthalmitis and positive vitreous cultures. COMMENT
In the therapeutic response arm of the study, all 12
eyes developed clinical signs of endophthalmitis within Any intraocular procedure carries with it the inherent risk
48 hours of the injection of organisms. Vitreous of infection. Of particular concern with intravitreal in-
samples obtained 7 days after intravitreal vancomycin jection of triamcinolone is its immunosuppressive effect,
injection were culture-negative in all eyes. The severity which may make the eye more susceptible to infection.
of vitritis at the time of vitreous sampling was markedly In our model of experimentally induced bacterial en-
less in the eyes receiving triamcinolone plus bacteria dophthalmitis, we found that eyes injected with triam-
(none with 4⫹ vitritis) compared with the eyes receiv- cinolone have a significantly higher rate of culture posi-
ing bacteria alone (5 of 6 with 4⫹ vitritis) (P = .02) tivity after 7 days than those injected with the same
(Table 3). quantity of bacteria alone. In the absence of triamcino-
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Downloaded From: http://www.jamafacial.com/ on 02/07/2015lar microenvironment. Patients should be carefully se-
Table 3. Therapeutic Response Vitritis Score Results 7 Days lected and should be adequately informed regarding the
After Intravitreal Vancomycin Injection* risk of infection. The importance of careful sterile tech-
nique cannot be overemphasized, as well as the use of
With Triamcinolone Without
Vitritis Score† Acetonide Triamcinolone
single-dose vials to minimize the risk of inadvertent in-
oculation of the eye with bacterial contaminants. We ad-
4⫹ 0 5
vise caution when considering the use of intravitreal tri-
⬍4⫹ 6 1
P Value‡ .02
amcinolone in conjunction with intraocular surgery, given
the likelihood that bacteria are routinely introduced into
*Data are given as number of eyes with the corresponding vitritis score. the eye intraoperatively. Intravitreal corticosteroid in-
†Vitritis scores are explained in the “Methods” section. jection will likely continue to be an important therapeu-
‡Calculated using Fisher exact test. tic alternative for refractory macular edema and neovas-
cular maculopathies. However, careful risk-benefit
considerations are warranted in light of these findings.
lone, the host immune response successfully cleared the
infection within 7 days with much greater frequency. It
appears, in effect, that the inoculum size of organisms Submitted for Publication: July 29, 2004; final revision
required to produce sustained culture-positive infec- received October 25, 2004; accepted October 25, 2004.
tious endophthalmitis is reduced by the triamcinolone. Corresponding Author: David N. Zacks, MD, PhD, Retina
The immunosuppressive effect of intraocular corti- Service, Kellogg Eye Center, Department of Ophthal-
costeroids has also led to concern about their potential mology and Visual Sciences, University of Michigan Medi-
masking of early signs of endophthalmitis. In our study, cal School, 1000 Wall St, Ann Arbor, MI 48105 (davzacks
the inflammatory response in the triamcinolone group @umich.edu).
was delayed despite the fact that the final severity of in- Funding/Support: This study was supported by a re-
flammation was greater in eyes receiving triamcinolone. search grant from the Midwest Eye Banks and Trans-
This delayed immune response might help explain why plantation Center, Ann Arbor, Mich (Dr Zacks), and by
the bacterial inoculum is not as readily cleared from the Core Grant EY07003 from the National Eye Institute,
eye. That is to say, the organisms might have a longer Bethesda, Md (Drs Reed and Richards).
period to incubate and multiply within the eye in the pres-
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