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Endophthalmitis After Keratoprosthesis
Incidence, Bacterial Causes, and Risk Factors
Mahnaz Nouri, MD;
Hisao Terada, MD;
Eduardo C. Alfonso, MD;
C. Stephen Foster, MD;
Marlene L. Durand, MD;
Claes H. Dohlman, MD, PhD
Arch Ophthalmol. 2001;119:484-489.
ABSTRACT
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Objectives To determine the rate of endophthalmitis in a group of patients with
keratoprostheses and to analyze possible risk factors.
Methods A total of 108 patient eyes, operated on between 1990 and 2000 with
double-plated keratoprostheses, were analyzed with regard to the surface flora,
the incidence and cause of bacterial endophthalmitis or sterile vitreitis,
the keratoprosthesis design, prophylactic antibiotics, concomitant immunosuppression,
and preoperative diagnosis.
Results Surveillance cultures were obtained from 30 uninfected eyes. The flora
was similar to that reported in the normal population and did not vary significantly
with time. Thirteen cases of bacterial endophthalmitis occurred 2 to 46 months
postoperatively in the patient population that had been followed up for 2
months to 17 years (average, 3 years 4 months). The incidence was 39% in 13
patients with Stevens-Johnson syndrome, 19% in 27 patients with ocular cicatricial
pemphigoid, and 7% in 28 patients with ocular burns. Only 1 of the other 40
cases (consisting mostly of repeated graft failures in noncicatrizing conditions)
developed endophthalmitis; this patient had a filtering bleb. All endophthalmitis
pathogens were gram positive: Streptococcus pneumoniae,
23%; other streptococci, 39%; Staphylococcus aureus,
23%; and Staphylococcus epidermidis, 15%.
Conclusions The most important risk factor for endophthalmitis after these keratoprostheses
was found to be preoperative diagnosis. The rate of infection was very high
in Stevens-Johnson syndrome and ocular cicatricial pemphigoid, moderate in
chemical burns, and low in noncicatrizing corneal disease.
INTRODUCTION
PATIENTS blinded by severe ocular surface diseases or injuries may become
sighted again through the placement of a keratoprosthesis (KPro); however,
because this device bridges the nonsterile ocular surface and the sterile
anterior chamber, the risk of intraocular infection is always present.1 Although endophthalmitis is known to occur frequently
in patients with KPros,2-3 the
incidence, bacterial causes, and risk factors for KPro-related endophthalmitis
have been insufficiently quantified.
Risk factors for any infection that involves a prosthetic device include
factors relating to the host, the device design, and the bacteria causing
the infection. The specific questions addressed herein were as follows: Are
patients with certain underlying ocular diseases at greater risk for KPro-related
endophthalmitis? Are some KPro designs associated with a higher incidence
of endophthalmitis? What bacteria are the most common causes of KPro-related
endophthalmitis, and are these bacteria more prevalent in uninfected KPro
ocular surface flora than in normal eyes?
We report our experience with 108 patient eyes with double-plated KPros,
including 13 patients who developed endophthalmitis. We also report the results
of surveillance cultures from 30 uninfected eyes.
PATIENTS AND METHODS
PATIENTS
A total of 108 patient eyes in 103 patients with various preoperative
diagnoses had a KPro implanted between March 1990 and January 2000. Ninety-six
eyes were operated on at the Massachusetts Eye and Ear Infirmary in Boston
and 5 were operated on outside the United States (by C.H.D.). In addition,
7 patients were operated on at the Bascom Palmer Eye Institute in Miami, Fla
(by E.C.A.). The patients were divided into 4 broad categories based on preoperative
diagnosis. Twenty-seven patient eyes had ocular cicatricial pemphigoid (OCP),
13 had Stevens-Johnson syndrome (SJS), and 28 had been burned (27 chemical
burns and 1 thermal burn). The remaining 40 patient eyes (other) had a variety
of noncicatrizing ocular conditions such as repeated graft failures from degenerations,
dystrophies, herpes simplex, herpes zoster, bacterial infection, aniridia,
rheumatoid arthritis, or graft-vs-host disease. As a rule the last group had
minimal intraocular inflammation in the past but had had repeated corneal
graft failures. The mean duration of follow-up for the total population was
3 years 4 months (range, 2 months to 17 years).
Bacterial endophthalmitis was recognized by sudden onset of ocular pain,
intensely inflamed eyes, and rapid reduction of vision. There was early severe
turbidity in the anterior chamber or the vitreous. Of the 13 patients who
had endophthalmitis, 9 received prompt therapy, including intravitreal antibiotics.
Therapy included intravitreal vancomycin, 1 mg; amikacin, 0.4 mg; dexamethasone,
0.4 mg; and topical and systemic antibiotics (intravenous vancomycin plus
ceftazidime, tobramycin, or ciprofloxacin). In 2 patients (1 and 5) no intravitreal
antibiotics were given before loss of vision, and in 2 others (3 and 4) intravitreal
therapy was delayed by at least 24 hours.
The institutional review boards had approved the project, and informed
consent was obtained from all participating subjects.
PROSTHESIS
The KPros were of the Dohlman-Doane design, which comes in 2 types (Figure 1).4
Type I has a collar button shape with a front plate diameter of 5.5 to 7 mm,
a stem diameter of 3.2 or 3.5 mm, an interplate distance of 0.75 or 1.0 mm,
and a back plate ranging from 7.0 to 11.0 mm. The type II prosthesis has the
same dimensions but with an additional 2-mm nub added to the front plate for
protrusion through the eyelid skin in end-stage dry conditions. The type I
keratoprosthesis was used in 65 eyes and type II in 43 eyes. In 57 cases the
back plate had holes to improve nutrition, fluid flow, fixation, and anchorage
by means of scar tissue formation. Fifty-one cases used a later design, the
"no holes" KPro, and nearly all (96%) such KPros were placed after October
1, 1996.
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Figure 1. Designs of keratoprostheses. Left,
Collar button–shaped device used in eyes with functioning tear secretion
and blink mechanism (type I). Right, Model with an added nub to protrude through
the lid skin in end-stage dry eyes (type II). In some back plates the holes
have been eliminated.
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SURGICAL PROCEDURE
The surgical techniques have been previously described in detail.5
ANTIBIOTICS, CORTICOSTEROIDS, AND IMMUNOSUPPRESSIVES
The patients routinely were given 1.0 g of cefazolin intravenously (except
in penicillin-allergic patients) at the start of the KPro operation. Topical
10% povidone-iodine was used as a preoperative antiseptic. Intraoperatively,
a topical combination product of trimethoprim and polymyxin B was administered
periodically. Postoperatively, the patients received oral cephalexin, 500
mg, 2 to 3 times daily by mouth for 2 to 3 weeks and topical gentamicin, ofloxacin,
or trimethoprim–polymyxin B. These were given 4 times a day initially
and gradually reduced to twice daily for 2 months. This regimen was then continued
indefinitely. Usually topical antibiotics were alternated every 3 months.
In the type I KPro, a temporary conjunctival flap was often used, and
this was opened centrally after 2 months.6
Before this opening, the antibiotics were given as indicated, accompanied
by 1% prednisolone acetate 2 to 4 times daily. Following exposure of the KPro,
whether from the time of surgery or after some time, the prednisolone was
switched to 1% medroxyprogesterone suspension 4 times daily. Standard long-term
dosage was twice daily. Only rarely was prednisolone given once the prosthesis
had been exposed.
Azathioprine or cyclosporine was given for a short time after the surgery
in 3 patients with a diagnosis of SJS. Similarly, azathioprine or dapsone
was given in 3 patients with OCP. In 4 patients systemic prednisone was also
administered for some time after the operation. At the time of infection,
however, corticosteroids and immunosuppressives were only administered as
indicated in Table 1.
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Table 1. Bacterial Endophthalmitis in Patients With Keratoprostheses*
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CULTURES
In a subset of 30 of the Massachusetts Eye and Ear Infirmary patient
eyes with KPros, we studied the microbial flora of the tissue around the device
(conjunctival in type I, lid skin in type II), obtaining cultures at various
times postoperatively. Patients had between 1 and 5 cultures taken at random
time points. The samples were placed on blood agar, chocolate agar, Sabouraud
agar, ANA agar, or in thioglycolate broth. The cultures were obtained after
1 drop of topical anesthetic was applied.
In patients with endophthalmitis, samples of aqueous humor and/or vitreous
were cultured for bacteria and fungi.
STATISTICS
All analyses were performed using the  2 test and Fisher
exact test. All tests were 2-sided with a .05 level of significance.
RESULTS
The results of surveillance cultures in 30 uninfected eyes (28 patients)
with KPros are shown in Table 2.
A second culture, performed several months later in 21 of these patients,
showed patterns of microbial growth similar to the first culture. The predominant
organisms were coagulase-negative staphylococci (present in more than two
thirds of eyes), Staphylococcus aureus, Corynebacterium species (diphtheroids), and viridans streptococci.
Gram-negative bacilli and yeast were uncommon.
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Table 2. Results of Surveillance Cultures of Ocular Surface Flora Taken
at 2 Time Points in 30 Uninfected Eyes With Keratoprotheses*
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Bacterial endophthalmitis occurred in 13 patients (Table 1, Figure 2). Possible
risk factors, such as preoperative corneal diagnosis, type of KPro, size of
back plate, and presence or absence of holes in the back plate, are listed.
Patients' medication at the time of infection and the causative organism are
also shown. The interval between surgery and infection varied between 2 and
46 months (average, 18 months).
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Figure 2. Examples of type I keratoprosthesis.
A, Successful outcome, 20/25 vision. B, Beginning necrosis and melt of cornea
between the plates. C, Severe, sudden endophthalmitis in a patient with Stevens-Johnson
syndrome with a 2-day history, which resulted in enucleation.
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The endophthalmitis rate in the total cohort was 12% (Table 3). The patients with SJS had a 39% incidence; the patients
with OCP, 19%; the burn patients, 7%; and other, 2%. 2 Analysis
of the disease categories revealed significant difference (P = .001). Further analyses showed significance regarding SJS vs burn
(P = .02) and SJS vs other (P
= .001). There was also statistical significance between OCP and other (P = .03). Although the difference in infection rate between
OCP and SJS appeared to be clinically important, it failed to meet statistical
significance (P = .13). The same held for OCP vs
burn (P = .20).
With regard to other possible risk factors for endophthalmitis, there
was no significant difference in patients who had a type I vs type II KPro
(7/65 or 11% vs 6/43 or 14.0%, respectively, P>.05).
Patients who had KPros with back plate holes had a higher rate of endophthalmitis
than those with the "no holes" design (9/57 or 16% vs 4/51 or 8%), but this
difference was not statistically significant (P>.05).
In addition, any difference in these rates may be ascribed to the shorter
duration of follow-up in patients with the "no holes" design. Patients who
had KPros with a larger back plate diameter ( 9.5 mm) had a higher rate
of endophthalmitis than those with back plate diameter of 8.5 mm or less (7/47
or 15% vs 6/61 or 10%), but this difference also was not statistically significant.
Thus, the only significant risk factor for endophthalmitis was preoperative
diagnostic category (SJS, OCP, burn, or other). Of note, the only 2 burn patients
who developed endophthalmitis had alcohol and compliance problems. Finally,
in the other group, the only patient who developed an infection also had a
glaucoma filtering bleb, a known risk factor.
The pathogens that caused endophthalmitis in our patients with KPros
are listed in Table 1. All endophthalmitis
cases were due to gram-positive cocci. In most cases, endophthalmitis resulted
in loss of useful vision (Table 3).
In 3 cases some vision was retained at the 20/400 to 20/200 level. In 2 of
these patients, the pathogen was Staphylococcus epidermidis and the third case was caused by viridans streptococci (Streptococcus mitis). This patient was seen within 6 hours of symptom
onset.
Several patients developed vitreous inflammation without pain or conjunctival
injection and responded to topical steroid therapy alone. They were diagnosed
as having sterile endophthalmitis (Table
3).
COMMENT
With our KPros and our techniques, endophthalmitis is now clearly the
main obstacle to a safe outcome. It used to be that glaucoma was the most
feared long-term problem, especially in the chemical burn category. However,
with the addition of the simultaneous implantation of a glaucoma valve shunt,
the threat of pressure damage has receded.7
In our series, the major risk factor for endophthalmitis was a preoperative
diagnosis of SJS or OCP. The reason for this is not clear. One possibility
is that patients with these conditions have an increased rate of tissue breakdown
("melt") around the KPro (Figure 3).
In most of the endophthalmitis cases, however, there was no visible leak of
aqueous humor at the time of infection and intraocular pressure was normal.
Microscopic bacterial contamination of the aqueous humor most likely occurs
in all KPro patients, and perhaps patients with SJS and OCP, in whom ocular
immunity may be altered, are less able to fight this microbial invasion.
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Figure 3. Examples of type II keratoprosthesis.
A, Stable situation after 6 years in a patient with ocular cicatricial pemphigoid
and 20/30 vision. B, Beginning skin retraction.
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The term vitreitis, in contrast to endophthalmitis
of clearly bacterial origin, requires some comment. Can we be certain that
patients with vitreitis are sterile? Admittedly not, but they constitute a
strikingly different category in that the eye is not red or painful and that
vision, with the aid of corticosteroids, returns to the previous level within
a few months. There are reasons to believe that some of these patients ignored
the recommendation to wear a protective shield during the night and probably
rubbed their unprotected eyes, causing a "spill" into the anterior chamber
of necrotic material that frequently accumulates between the 2 KPro plates.
The holes in the back plate may play a role here, and because of this suspicion,
the back plates are now made solid.
All endophthalmitis cases in our series were due to streptococci or
staphylococci, but KPro patients with SJS and OCP in our surveillance culture
group did not have a higher rate of colonization with these organisms than
other KPro patients. Some pathogens were not found in the surveillance cultures,
and it is likely that once colonization with these intrinsically virulent
organisms occurs, infection follows rapidly. This seemed to be true for Streptococcus pneumoniae and  -hemolytic streptococci,
organisms not found in surveillance cultures. Indeed, 1 patient (patient 4)
in the surveillance group developed pneumococcal endophthalmitis 3 weeks after
a surveillance culture grew only  -streptococci (S mitis) and coagulase-negative staphylococci.
Endophthalmitis due to streptococci or S aureus
is associated with a poor outcome in postcataract endophthalmitis.8 All 10 of the patients with endophthalmitis in our
series infected with these organisms lost all vision in the affected eye.
The 3 patients who had some salvage of vision had either S epidermidis, an organism associated with a good outcome in postcataract
endophthalmitis, or presented very early (within 6 hours of symptom onset).
Postoperative endophthalmitis is clearly a major obstacle in patients
with SJS and OCP. In fact, the results in our patients with SJS have been
so poor that we are hesitant to perform KPro surgery in this category at the
present time. On the other end of the spectrum, the burn patients and, particularly,
the graft failures have shown infection rates that are quite low, considering
the often severe conditions. Under any circumstances, the search for more
effective preventive measures must be intensified. Pneumococcal vaccination
may prevent some of the pneumococcal endophthalmitis cases (E. Hohmann, MD,
oral communication, 1999). Since all of the infections were due to gram-positive
cocci, topical vancomycin may be indicated instead of, or in addition to,
other antibiotics. Swabbing around the type II KPro periodically with hydrogen
peroxide or with povidone-iodine may also reduce organism colonization and
the need for topical prophylaxis. When tissue melt is threatening the integrity
of the device, repair surgery should be effectuated promptly and the procedures
should be refined to make them more simple and effective.
The role of postoperative corticosteroids is not clear, but perhaps
their use should be kept at a minimum. In animal experiments, topical corticosteroids
reduce the stability of KPros.9 These are important
issues to resolve since sustained corticosteroid treatment postoperatively
in the form of topical drops and sub-Tenon injections are usually required
to prevent prolonged intraocular inflammation and formation of retroprosthesis
membranes. Clearly, continued efforts to prevent infections after KPro implantation
must be given high priority.
AUTHOR INFORMATION
Accepted for publication September 27, 2000.
This work was supported by Dysautonomia Foundation, Inc, New York, NY.
The authors are indebted to Balraj Jhawar, MD, for statistical analysis.
Corresponding author: Claes H. Dohlman, MD, PhD, Massachusetts Eye
and Ear Infirmary, 243 Charles St, Boston, MA 02114.
From the Departments of Ophthalmology, Massachusetts Eye and Ear Infirmary,
and Harvard Medical School, Boston (Drs Nouri, Terada, Foster, Durand, and
Dohlman); and Bascom Palmer Eye Institute and University of Miami School of
Medicine, Miami, Fla (Dr Alfonso). The authors have no proprietary interest
in any device described in this article.
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