BY Travis A. Meredith, MD, H. Edith Aguilar, MD (BY INVITATION)

17 Pages·2005·1.41 MB·English

INTRAOCULAR DEXAMETHASONE PRODUCES
A HARMFUL EFFECT ON TREATMENT OF EXPERIMENTAL
STAPHYLOCOCCUS AUREUS ENDOPHTHALMITIS*
BYTravisA. Meredith, MD, H. EdithAguilar, MD (BYINVITATION),
Carolyn Drews, PhD (BYINVITATION), Anil Sawant, PhD (BY INVITATION),
Suzanne Gardner, DPharm (BY INVITATION),
LouisA. Wilson, MD (BY INVITATION), AND
Hans E. Grossniklaus, MD (BYINVITATION)
ABSTRACT
Background: We created a standardized model ofsevere Staphylococcus
aureus endophthalmitis intheaphakicrabbiteyetotestvarioustreatment
strategies involvingcorticosteroid administration in additiontovitrectomy
andantibiotic treatment.
Materials and Methods: In 71 aphakic New Zealand albino rabbit eyes,
experimentalendophthalmitiswascreatedbyinjecting 105colony-forming
units of Staphylococcal aureus. The animals were divided into 5 groups.
One control group was followed up without treatment, while 4 groups
were treated with vitrectomy and intraocular cefazolin injection. Two
groups were also treatedwithintramuscular methylprednisolone, 1 group
beginning on the dayofsurgery and 1 group beginning on the following
day. In the final group, dexamethasone, 400 jig, was injected into thevit-
reous cavityatthe close ofsurgery. Culture resultswere compared onthe
first 2 days after surgery. Inflammatory scores, including development of
total comeal opacity, were assessed over a 21-day follow-up period, and
histopathologic grading was carried out at the conclusion ofthe clinical
observations.
Results: Simultaneous administration of systemic corticosteroids begin-
ningonthedayofvitrectomy decreasedinflammatoryscores 1weekafter
institution oftherapybut didnot affectfinalscores. Delayofinitiation of
intramuscular corticosteroid until the first postoperative day negated the
'From St Louis University School of Medicine (Dr Meredith and Dr Aguilar), St Louis,
Missouri, and Emory University Medical School (Drs Meredith, Aguilar, Drews, Gardner,
Wilson, andGrossniklaus), Atlanta, Georgia, andthe DepartmentofMicrobiology, Georgia
State University (Dr Sawant), Atlanta. Supported by grant ROI EY-0574-0441 from the
NationalInstitutesofHealth.
TR.AM. OPHTH. SOC.VOL.XCIV, 1996
242 Meredith
positive effects. Administration ofintraocular corticosteroids was associ-
ated with an increase in inflammatory scores throughout the period of
observation, an increase in percentage of eyes that developed opaque
corneas, anincreaseinchoroidalinflammationgradedmoderateorsevere,
andanincreaseinretinalnecrosiscomparedwithvitrectomyandcefazolin
injection alone.
Conclusions: This datasuggest caution inthe use ofintraocularcorticos-
teroids intreatment ofsevere endophthalmitis.
INTRODUCTION
Intraocularinfection and inflammation destroyvital ocularstructures and
oftenresultin lossoffunctionalvision. Outcomeisdeterminedbyanum-
ber of factors, the most of important ofwhich may be virulence in the
infecting bacteria. Control of bacterial replication is important in suc-
cessful treatment butis notnecessarily sufficient toproduce agood func-
tional outcome.
Controlofinflammation, inadditiontoeradicationofbacteria, maybe
important in final visual outcome; corticosteroids have long been advo-
cated as adjunctive therapy in the management ofendophthalmitis."2 In
studiesoftreatmentofchildhoodmeningitis (aclosed-spaceinfectionwith
similarities to endophthalmitis in pathogenesis and treatment), simulta-
neous administration of systemic dexamethasone concomitant with the
administration ofparenteral antibiotic reduces the number oflong-term
neurologic sequelae.3" Corticosteroids have anumber ofpotentiallyben-
eficialactions, includingdecreasing prostaglandin productionandinhibi-
tion ofcytokines such as tumor necrosis factor (TNF) and interleukin-I
(IL-1).6
Graham andPeyman2 suggestedthatintraocularcorticosteroids might
improvevisual resultswhen usedtotreat endophthalmitis. Intheirstudy,
intravitreal corticosteroid administration improved outcome only when
administered within 8 hours of inoculation ofbacteria into the vitreous
cavity. The administration ofcorticosteroids andantibiotics concomitantly
24 hours afterinoculation ofbacteriadidnotimprove outcome. In apre-
vious model ofStaphylococcus epidermidis endophthalmitis, we reported
that the administration ofintraocular corticosteroids or systemic corticos-
teroids was associatedwith improvedinflammatoryscores throughout the
posttreatment course. The intraocular routehad no significant advantage
overthesystemicrouteinthis study,however.7 Recentstudies8-10 havealso
suggested improvement in several outcome measures when eyes treated
without vitrectomywere given intravitreal corticosteroids and intravitreal
IntraocularDexamethasone inExperimental Endophthalmitis 243
antibiotics. Thus we studied the administration ofcorticosteroids in con-
junction with vitrectomy and intravitreal antibiotic injection in a rabbit
model of severe aphakic S aureus endophthalmitis. We have previously
reported that vitrectomy and cefazolin provided a better outcome in this
model when a number ofparameters were comparedwith controls." In
this report, we compare three strategies of concomitant corticosteroid
administration totryto furtherimprove measures ofoutcome.
MATERIALS AND METHODS
To assess the role ofcorticosteroids as an adjunctive therapyto the basic
strategyofvitrectomyandantibiotic injection,we createdamodelofbac-
terialendophthalmitis byinjecting 105colony-formingunitsofalaborato-
ry strain of S aureus into aphakic rabbit eyes and evaluated 3 different
strategies of corticosteroid administration. Seventy-one eyes of New
Zealand rabbits weighing 2.5 to 3.0 kgwere used in this study. The lens
was removedbyultrasonic fragmentation bypars plans lensectomy.
Three weeks were allowed to pass for healing from the surgery, and
the eyes were then examined before proceeding to create experimental
infection. S aureuswas then injected into the midvitreous cavity, andthe
eyeswere reexamined24hourslaterandgraded clinically. Theeyeswere
assignedto 1 of5 different groups: (1) untreatedeyes, (2)vitrectomyplus
intraocular cefazolin (15 eyes), (3) vitrectomy, intraocular cefazolin, and
intramuscular methylprednisolone succinate, 25 mgper0.2 mL adminis-
teredfor5 days beginningonthe dayofsurgery (13 eyes), (4) vitrectomy,
intraocular cefazolin, and methylprednisolone succinate administered for
5 days beginning on the dayfollowing surgery (11 eyes), and (5) vitrecto-
my, intraocularcefazolin, andintraocularinjection ofdexamethasone, 400
pg (17 eyes). All treatmentwas initiated 24 hours afterbacteria inocula-
tion in eyes which demonstrated unequivocal and similar signs ofclinical
infection.
To perform vitrectomy, a 20-gauge needle was used for perfusion of
balanced salt solution; with a suction cuttingprobe, the inflamed, abnor-
mal material of the anterior chamber and the fibrin membrane was
removed from the surface of the iris. Central and anterior vitrectomy
were performed, takingcare to removevitreous from the undersurface of
theiris. Noattemptwasmadetoremovevitreousfromtheretinalsurface.
Forall surgery, rabbitswere anesthetizedwitha50/50mixture ofxylazine
hydrochloride (20 mg/mL) and ketamine hydrochloride (100 mg/mL) by
intramuscularinjection. Phenylephrine hydrochloride 10% andcyclopen-
tolate hydrochloride 1% were used to dilate the pupils. Animals were
maintained in accordance with the resolution on animal use of the
244 Meredith
Association forVision and Research in Ophthalmology.
Cefazolin sodium, 2.25 mg per 0.1 mL balanced salt solution, was
injected into the vitreous cavity in all eyes in the 4 treatment groups.
Methylprednisolone sodium succinate, 25 mg per 0.2 mL, was injected
intramuscularlyfor5daysingroups3and4. Dexamethasone,400jig,was
injectedinthe midvitreous cavityatthecloseofthevitrectomyingroup5.
Clinical grading was carried out as previously described in all eyes
prior to treatment, and 7, 14, and 21 days after treatment.'" All animals
were anesthetized on the first and second days aftertreatment, andvitre-
ous was aspirated from the midvitreous cavity, removing 0.2 to 0.3 cc
through a23-gauge needle forquantitative culture. Thevitreous samples
were seriallydiluted andplatedin triplicates ontotryptic soyagar (Difco)
plates. After incubation of24 to 36 hours at 370C, lack of colonies on
plates with the first tenfold dilution was considered a negative culture
result. Eyeswere includedinthe studyonlyiftheydemonstratedclinical
infection and had a positive culture either before treatment or at one of
the two posttreatment cultures.
At the conclusion of21 days ofclinical observation, the majority of
eyes were enucleated for histopathologic study. Sections were stained
withhematoxylin-eosinandexaminedbyanocularpathologistwhodidnot
knowthe clinical management ofthe eye. Inflammation was classified as
acute orchronic and a grading ofmild, moderate, or severe was assigned
for6 areas ofthe eye: cornea, iris, ciliarybody, choroid, retina, andvitre-
ous. Notation ofretinal necrosis was also made.
We evaluated culture results on days 1 and 2 aftertreatment; inflam-
matory scores 7, 14, and 21 days after surgery; the percentage of eyes
developing corneal opacity 3 weeks after therapy; and histopathologic
changes inthe eyes 3weeks afterinitiation oftherapy.
Weusedthe BMDPstatistical softwaretoanalyzeourdata. Repeated
measures analysis ofvariance (ANOVA) was used to compare the influ-
ence oftreatment on inflammatory scores. Data on inflammation were
also dichotomized. An inflammatory score of24 or higher was possible
onlywith an opaque cornea. The effectoftreatmentonthe riskofopaci-
tywas examinedwith aPearson's chi-square, andthe impactoftreatment
modalityonthe rate atwhich opacities developedwas examinedusinglife
table approach; a cornea was considered to remain opaque once the
inflammatory score reached 24, regardless of any observed decrease in
inflammatoryscore. Directcomparisons between subgroupswas evaluat-
edwith Fisher's exacttest.
Analysis ofthe impact oftreatmenton the occurrence ofpositive cul-
tureswas conductedin asimilarmannerto analysis ofthe riskofopacity.
IntraocularDexamethasone in Experimental Endophthalmitis 245
RESULTS
We have previously reported that vitrectomy and intraocular cefazolin
reduced the inflammatory scores and the percentage ofeyes developing
corneal opacity; the number ofculture-positive results decreased com-
pared with no treatment." Treatment with intramuscular corticosteroids
beginning on the dayofsurgery further reduced the inflammatory scores
onday7 (untreated, 24;vitrectomypluscefazolin, 19; cefazolinplusintra-
muscular corticosteroid, 14.5). The inflammatory scores in the corticos-
teroid group remained stable at this level over the subsequent 14 days,
while the eyes treatedwithout corticosteroids showed an improvement in
inflammatory scores byday21, so there was not a final significant differ-
encebetweenthe2groups (Table I). Therewas nosignificantdifference
intheculture-positive results at48hoursbetweenthe2groups (Table II).
The percentage ofeyes with opaque comeas was essentially the same at
21 days in these 2 comparative groups (corticosteroid, 27%; no corticos-
teroid, 31%) (Table III). Histopathologic examination ofthe eyes treated
withcorticosteroidsshowedasignificantincreaseinthepercentageofeyes
demonstrating retinal necrosis (72% versus 27%; P=0.003), but no other
significant differences.
Delayofinitiation ofintramuscularcorticosteroid by 1 dayresultedin
thegroupofeyeswithcorticosteroidtreatmenthavingessentiallythesame
inflammatoryscores on day7andthroughouttheperiodofobservationas
theeyes receivingvitrectomyandcefazolintreatment. Thepercentageof
culture-positive results on posttreatment day 2 was equivalent (48% ver-
sus 43%), and the percentage ofeyes with opaque corneas at day21 was
not statistically significantly different (27% versus 37%). On histopatho-
logicevaluation, the delayedcorticosteroidgroupshoweddecreasednum-
bers of eyes with severe vitreous reaction (55% versus 22%), but an
increase inretinalnecrosis (56%versus 20%) andanincreaseinmoderate
or severe choroidal reaction (56% versus 18%), although none of these
effectswas statisticallysignificant.
Whencorticosteroidwasadministeredintothevitreouscavityattheclose
ofthesurgicalprocedure,theinflammatoryscoresremainedstableandequiv-
alent to the pretreatment scores, while the inflammatory scores in all other
treatment groups decreased. Comparing the eyes treated with surgery and
intraocularcorticosteroidwiththosethatreceivednocorticosteroid, therewas
anincreaseofcomealopacityatthecloseoftheperiodofevaluation (27%ver-
sus 69%; P=.0.03). On histopathologic evaluation, the group treated with
intraocular corticosteroids showed an increase in eyes demonstrating retinal
necrosis (27%versus 100%;P=0.0001) andanincrease inmoderatetosevere
choroidalinflammatoryreaction (18%versus 70%;P=0.03).
246 Meredith
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DISCUSSION
Reduction ofinflammation remains an important part ofmanagement of
endophthalmitis. In the Endophthalmitis Vitrectomy Study, all treated
patients receivedsystemiccorticosteroids. InthisSaureus modelofsevere
endophthalmitis andourmodel ofSepidermidis endophthalmitis,7 bene-
ficial effects ofearlyintramuscular administration in eyes treatedwithvit-
rectomyandintraocularantibioticswere demonstrated.
Several investigators have studied the effects ofaddition ofintraocu-
larcorticosteroids tointravitrealantibioticinjectioninexperimental infec-
tions treated without surgery. Jett and coworkers10 demonstrated that
treatment with intraocular corticosteroids and antibiotics produced abet-
ter outcome when evaluated by electroretinography and histopathology
thanantibioticinjection aloneinamodelofendophthalmitis producedby
a toxin-producing strain of Enterococcus faecalis. This improvement,
however, was strain-dependent anddidnotoccurwheninfectionwaspro-
duced by a toxin-producing strain ofEnterococcus. Park and associates9
also demonstrated a beneficial effect for intraocular corticosteroid injec-
tion in a model ofpneumococcal endophthalmitis. Studies ofS epider-
midis endophthalmitis noted beneficial effects from intraocular corticos-
teroids;8 although our model ofsevere S aureus endophthalmitis failed to
show such a benefit.1' Clinical studies by Mao and coworkers'2 showed
good treatment outcomes inpatients infectedwith Saureus whose thera-
pyincluded intraocular corticosteroids. Although this was not a random-
izedstudy, directcomparisons between intraocularandsystemicadminis-
tration demonstrated no advantage forthe intraocularroute.
Inthis model,we assessedadditionofcorticosteroids tothetreatment
strategyofvitrectomyandintraocularcefazolininjectioninanexperimen-
tal model of severe aphakic S aureus endophthalmitis. The most suc-
cessful strategy was beginning intramuscular corticosteroid injection on
the day ofthe surgical intervention. This produced a faster decrease in
inflammatory scores but did not improve the final outcome measured by
inflammatory scores or the percentage of eyes developing complete
corneal opacity. More eyes demonstrated retinal necrosis. Interestingly,
all eyes remained culture-positive on day 1, suggesting the possibility of
continued toxin production as a cause for the intraocular inflammatory
changes.
Delayofcorticosteroidadministration untilthefirstpostoperative day
negatedthepositiveeffectsofintramuscularcorticosteroidadministration.
Therewerenomeasures ofoutcomethatshowedimprovementcompared
with surgeryandantibiotic injection alone.