Late Bacterial and Fungal Keratitis after Corneal Transplantation

Late Bacterial and Fungal I(eratitis after Corneal Transplantation Spectrum of Pathogens, Graft Survival, and Visual Prognosis DAVID J. HARRIS, Jr., MD, R. DOYLE STULTING, MD, PhD, GEORGE O. WARING III, MD, LOUIS A. WILSON, MD Abstract: The authors reviewed 108 bacterial and fungal corneal ulcers that developed 1 to 72 months after penetrating keratoplasty in 79 eyes of 78 patients. Graft hypesthesia, topical corticosteroid and antibiotic treatment, exposed sutures, epithelial defects, and poor visual acuity commonly predated infectious keratitis. There were 69 bacterial, 34 fungal, and 5 combined infections. Candida albicans and Staphylococcus epidermidis were the most common pathogens. Follow-up after infection averaged 23 months (range, 1-80 months). Despite hospitalization and fortified topical antibiotic treatment, complications such as wound dehiscence and corneal perforation necessitated emergency regraft in 38 (35%) cases. Of 73 previously clear grafts, only 29 (40%) retained clarity. Median visual acuity, 20/200 before infection, fell to counting fingers at last follow-up; 12 eyes lost light perception. [Key words: Candida albicans, corneal transplantation, corneal ulcer, fungus, keratitis, keratoplasty, prophylactic antibiotic, Streptococcus epidermidis, therapeutic contact lens.] Ophthalmology 95: 1450-1457, 1988

Infectious keratitis that occurs in the early postoperative period after penetrating keratoplasty may arise from recurrent host disease, infected donor material, or intraoperative contamination. In contrast, late infectious kerOriginally received: November 9, 1987. Revision accepted: June 14, 1988. From the Department of Ophthalmology, Emory University School of Medicine, Atlanta. Dr. Harris is currently with the Department of Ophthalmology, Bethesda Naval Hospital, Bethesda, Maryland.

atitis is probably caused by environmentally acquired pathogens. We studied 108 cases of late graft infection that presented at Emory Eye Center between 1980 and 1987 in order to evaluate the spectrum of pathogens, the prognosis for graft clarity, and the visual outcome. We also sought to identify the clinical settings in which keratitis most commonly occurred. We present our findings as they apply to the group as a whole and analyze differences among subgroups within the series. We then compare our results to previously reported cases and suggest methods of prevention, diagnosis, and management.

Presented at the American Academy of Ophthalmology Annual Meeting, Dallas, November 1987. Supported in part by a department grant from Research to Prevent Blindness, Inc.

MATERIALS AND METHODS

Reprint requests to R. Doyle Stulting, MD, PhD, Emory University School of Medicine, Department of Ophthalmology, 1327 Clifton Rd, N.E., Atlanta, GA 30322.

The records of Emory University Hospital were searched for all cases (occurrences) of bacterial or fungal

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Table 1. Preoperative Diagnoses Diagnosis Fuchs' dystrophy Aphakic corneal edema Pseudophakic corneal edema Herpes simplex keratitis Scar (other than herpes) Keratoconus Exposure keratopathy Sjogren's syndrome Herpes zoster Aniridia Other

-... o GJ

.a

E ~

z

45 40 35 30 25 20 15 10 5

No. of Cases (%)

23 (21) 19 (18) 15 (14) 15 (14) 14 (13) 5 (5) 5 (5) 3 (3) 2 (2) 2 (2) 5 (5)

42

single organism were recovered. Since most corneal scrapings were initially inoculated onto only chocolate and Sabouraud's media, we did not require growth on two different media to be a criterion for positive cultures. Statistical analyses of visual acuity were carried out using the Wilcoxon rank sum test, whereas other frequency data were compared with 2 X 2 contingency tables and chi-square analysis.

RESULTS One hundred eight cases of late infectious keratitis involving 79 eyes of 78 corneal transplant patients were reviewed. Table 1 lists the preoperative diagnoses. In 14 cases, the most recent transplant was performed because of a previously failed graft. Seven eyes (in addition to those grafted for direct complications of keratitis sicca) were diagnosed to have Sjogren's syndrome, but results of quantitative testing for tear production were not available in many cases. Sixty eyes had only one occurrence of infectious keratitis; 13 eyes had 2; 3 eyes had 3; 2 eyes had 4; and 1 eye had 5. The average age at presentation was 64 years (range, 1-95 years). Sixty-one percent of ulcers occurred in females, and 54% involved right eyes. TIMING AND VISUAL ACUITY

0 0

6

12 18 24 30 36 42 48 54 60 66 72

Months After Corneal Transplantation Fig 1. Interval in months between most recent corneal transplant surgery and onset of bacterial or fungal keratitis in 108 cases.

keratitis supported by Gram stain, culture, or both, that occurred at least 1 month after the involved eye had received a corneal transplant. In general, infectious keratitis was suspected in these cases because of progressive corneal ulceration with surrounding cellular infiltrate and signs of intraocular inflammation. The following information was recorded for each case: age, sex, involved eye, original corneal diagnosis (before transplantation), date of most recent penetrating keratoplasty, clarity of the graft, visual acuity at the last clinic visit before onset of keratitis, corticosteroid and antibiotic usage, contact lens wear, date of presentation, symptoms at presentation, location of the ulcer, anterior chamber reaction, results of Gram stain of corneal scrapings, culture and sensitivity results, pharmacologic and surgical treatment used, immediate and delayed complications, fate of the involved graft, and date and visual acuity at the most recent examination. A clear graft was defined as one with compact central stroma without epithelial or stromal edema that allowed a clear (20/40 or better) view of iris detail. A graft was considered to have failed if it was not clear. A positive culture was defined as growth of more than one colony of an organism in the inoculating streak of any culture medium. In most cases, many colonies of a

The median interval between penetrating keratoplasty and infection was 9 months (range, 1-72 months). Fortytwo (39%) infections occurred in the first 6 months after surgery. The incidence steadily declined thereafter, except for a small increase in cases occurring 25 to 30 months postoperatively (Fig 1). Repeat infections occurred from I to 38 months after the previous infections (median, 8 months). Even in relatively early repeat infection, the records were adequate to rule out recurrence of incompletely treated ulcers. Median best-corrected visual acuity before infection, recorded in 95 cases, was 20/200 (range, light perception-20/20). Thirty-two grafts (30%) had failed before keratitis occurred. POSSIBLE PREDISPOSING FACfORS

Significant punctate keratopathy or frank epithelial defect predated the ulcer in 59 cases (55%). A contact lens had been prescribed for therapeutic purposes in 21 cases (19%) and for refractive purposes in 12 (11 %). Of these, nine were extended wear aphakic soft contact lenses and three were rigid gas-permeable contact lenses. In 33 cases (31 %), an exposed suture had been noted and/or removed within 10 days before infection or was present in association with a suture abscess at presentation. In all, 92 ulcers (85%) were associated with epithelial defect, contact lens use, or exposed suture. Many had combinations of these factors (Fig 2). Bacterial ulceration occurred in association with a herpetic epithelial dendrite in only one case. Ninety-six cases (89%) occurred in eyes receiving topical corticosteroid therapy. Seventy-five (69%) involved eyes that had received one of eight different topical antibiotics for at least 10 days (Table 2). Of these, 26 (35%) were 1451

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Contact Lens Wear

Epithelial Defect

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Table 2. Prophylactic Antibiotic Use

Exposed Suture

using a bacitracin/polymyxin combination; 22 (29%), chloramphenicol; and 21 (28%), gentamicin. Only 7 eyes (7%) were receiving neither corticosteroid nor antibiotic treatment, whereas 71 (66%) were receiving both. Most eyes being treated with antibiotics had been under antibiotic treatment since the most recent penetrating keratoplasty. SEASONAL OCCURRENCE AND SYMPfOMS

The incidence of infection was slightly greater during warm months, with 38 cases (35%) presenting in June, July, or August (Fig 3). In 27 cases (25%), patients noticed no discharge, pain, or visual loss related to keratitis. Of these, 21 presented simply for evaluation of a "white spot" noticed by the patient or relative on the involved eye, whereas the remaining 6 ulcers were seen during scheduled examinations. Symptoms noted by the other patients included decreased visual acuity, conjunctival discharge, redness, photophobia, foreign body sensation (especially with exposed sutures), generalized eye pain, contact lens intolerance, and sudden fluid discharge (from wound dehiscence or perforation). SIGNS

Infection involved the donor cornea either centrally or along suture tracts in all cases. No case involved the host cornea exclusively. The diameter of the infiltrate varied from less than 1 mm to the entire width of the graft. Likewise, depth of involvement varied from 5 to 100% of corneal thickness at presentation. Only one case presented as an intrastromal abscess with an apparently intact epithelium, and one case displayed crystalline morphology. Multiple infiltrates were documented in six cases (6%). Anterior chamber reaction was recorded in 78 cases. Of these, 18 (23%) had hypopyon, 40 (51 %) showed cellular reaction without hypopyon, and 18 (23%) showed no ceUs. MICROBIOLOGIC FINDINGS

Results of Gram stain of corneal scrapings were recorded in 87 cases (Table 3). In eight of these, no organism was isolated on culture. Of these culture-negative cases,

Antibiotic

No. of Cases

None Bacitracin/polymyxin Chloramphenicol Gentamicin Sulfacetamide Erythromycin Tetracycline (orally) Neomycin Cephalexin (orally) Unknown

32 26 22

17

2 2 2 1 1

3

Total

Fig 2. Distribution of common causes of breach of epithelial integrity before keratitis in 92 cases.

1452

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III

G)

III

as

0

...0

G)

Jl

E :l

Z

108

13

14 12

13

10 8 6 4 2

0 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

Month of Presentation Fig 3. Month of presentation in 108 cases of infectious keratitis after penetrating keratoplasty.

Table 3. Gram Stain Results Gram Stain Results Recorded Culture negative Culture positive Consistent with culture" No organism seen Conflicted with culture Total

No. of Cases (%)

8

79

61 (77) 14 (18) 4 (5)

87

• In three cases, only one of two cultured organisms was seen on Gram stain, leaving 58 (or 73%) Gram stains identifying all pathogens.

Gram stain showed fungi in four and bacteria in four. Referring physicians had begun broad-spectrum antibiotics before diagnostic studies in all four presumed bacterial cases. Of the remaining 79 cases, Gram stain was consistent with subsequent culture (Le., showed at least 1 implicated organism) in 61 (77%). Morphology representing all isolated organisms, even in multiple pathogen cases, was seen in 58 cases (73%). No organism was seen on Gram stain in 14 cases (18%). Gram stain interpretation conflicted with culture results in four cases (5%) (Table 3). Gram stain of one additional atypical mycobacterial case showed Gram-positive rods. Since mycobacteria usually appear Gram-positive, this

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Table 4. Organisms Isolated Organism

and generally unrevealing. Both strains of atypical mycobacteria seen in this series grew readily on chocolate agar. In 56 cases under long-term treatment with antibiotics in which sensitivity to that antibiotic was tested, resistant organisms were cultured in 50 cases (89%).

No. of Cases

Candida albicans Staphylococcus epidermidis Staphylococcus aureus Serratia marcescens Pseudomonas aeruginosa Streptococcus pneumoniae Proteus mirabHis Moraxella sp Candida parapsHosis Klebsiella oxytoca a Hemolytic streptococci Atypical mycobacteria Candida guilliermondii HaemophHus inffuenzae Enterobacter agglomerans Paecilomyces lilacanus Cryptococcus albidus Streptococcus sp Diphtheroids Penicillium sp Mold, species unknown

27

20

12 9 7

TREATMENT

6

6 5

4

3 2 2

2 1 1 1 1 1

1

1 1

Table 5. Multiple Pathogen Cases Organisms Isolated Bacterial Proteus mirabilis and Klebsiella oxytoca Staphylococcus aureus and Moraxella sp S. aureus and Staphylococcus epidermidis S. epidermidis and P. mirabilis S. epidermidis and Streptococcus sp

No. of Cases 2 1 1 1 1

Fungal Candida albicans and Cryptococcus albidus Combined C. albicans and S. epidermidis Mold and S. epidermidis PaecHomyces IHacanus and S. epidermidis C. albicans and Enterobacter agglomerans Candida parapsHosis, Penicillium, and S. epidermidis

2 1 1 1 1

case was not included among the four "conflicting" cases. Gram stain showed microbial morphology in seven of eight multiple pathogen cases in which Gram stain results were recorded. This corresponded to all cultured organisms in three cases, one cultured organism in three cases, and neither cultured organism in one case. Gram stain disclosed fungal elements in 20 (77%) of 26 fungal cases. Positive cultures were obtained from corneal scrapings in 100 cases (93%). Candida albicans (27 cases) and Staphylococcus epidermidis (20 cases) were the most common pathogens (Table 4). Two organisms were cultured in 12 cases and three in one case (Table 5). Anaerobic and other specialized media were infrequently used

Only three ulcers, all presenting in 1986 and 1987, were treated on an outpatient basis. These were small peripheral ulcers in dependable patients. The remaining patients were admitted to the hospital for around-the-clock applications of fortified topical antibiotics, singly or in combination. The physicians caring for the patients in this series used Gram-stain results to varying degrees in the selectioll of initial therapy, modifying treatment as necessary based on clinical course and culture results. Of the four cases in which morphology seen on Gram stain conflicted with subsequent culture, three were bacterial ulcers in which the initial treatment based on Gram stain was nevertheless appropriate. The fourth was a case in which pseudohyphae were seen on Gram stain and S. epidermidis later grew in culture. The physician in this case relied on the Gram stain and the lesion cleared on antifungal therapy, suggesting that S. epidermidis was a contaminant. In only three cases was it necessary to modify treatment based on Gram stain because of subsequent culture and sensitivity results. Two were mixed bacterial and fungal ulcers in which Gram stain showed only the bacterial component, and the third was the previously mentioned atypical mycobacterial case. Antecedent steroid therapy generally was discontinued in severe cases and maintained or reduced in less severe cases. Follow-up averaged 23 months after infection (range, 1-80 months). Immediate complications of infection included perforation in 20 cases (19%), wound dehiscence in 9 (8%), endophthalmitis (culture proven) in four (4%), and descemetocele in 3 (4%). In only three cases was graft rejection diagnosed within 7 days of infection. However, graft infiltration and severe anterior segment inflammation may have prevented diagnosis of rejection in some cases. Since antibiotic treatment successfully eradicated infection in all cases in which the structural integrity of the globe was maintained, no case required regraft for persistent infection. Of 73 previously clear grafts, 29 (40%) remained clear after resolution of infection (Table 6); none of these suffered subsequent allograft rejection. Of78 grafts that perforated or were failures after resolution of infection, 38 (49%) required emergency regraft, 16 (21 %) underwent elective keratoplasty, and 24 (31 %) received no further keratoplasties. Follow-up of more than 6 months was available on 62 of the 79 eyes. The median final visual acuity in these eyes was counting fingers; 12 eyes lost light perception. In 67 eyes for which visual acuity was known both before infection and after resolution of infection, the median loss of visual acuity was two Snellen lines (Fig 4). 1453

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Table 6. Fate of Graft After Infection Failed Elective Regraft

Status of Graft before Infection

Clear

Clear Failed Unknown

29 0 0

0

Total

29

16

9

7

The larger preoperative corneal diagnostic groups were evaluated for differences from the series as a whole. Those with endotheliopathies and nonherpetic scarring mirrored the average clinical profile; those with herpes simplex and keratoconus differed. The seven eyes with herpes simplex had very poor final visual acuity (median, light perception; P = 0.08). Keratoconus patients had excellent vision before infection (median, 20/25; P = 0.10) and after infection (median, 20/30; P = 0.08). Four of the five infections in keratoconus eyes involved sutures which had become exposed an average of 28 months after penetrating keratoplasty. In order to find any differences between early and late infections, the 55 ulcers occurring less than 10 months after penetrating keratoplasty were compared with the 53 that occurred later. Median visual acuity before infection was 20/400 in the early group and 20/80 in the late group (P < 0.001). Median final visual acuity was the same (counting fingers) in both groups, however. Interestingly, the frequency of corticosteroid use was similar in the early and late groups (87 and 91 %, respectively). Even though the early group was more likely to have been receiving antibiotics (83 versus 56%), there were no striking differences in the spectrum of offending organisms between the two groups. Sixteen (59%) of the 27 cases with no symptoms at presentation were fungal ulcers (P < 0.04). All asymptomatic cases were under steroid treatment at presentation, compared with 69 (85%) of the remaining 81 symptomatic cases (P = 0.09). Nineteen of 21 patients wearing therapeutic soft contact lenses (90%) were using antibiotics at presentation. Of these, 18 (95%) grew pathogens resistant to the antibiotics used. S. epidermidis appeared in nine cases (43%). Five of these occurred in patients treated with chloramphenicol; all were resistant to chloramphenicol (P < 0.00 1; control group: all S. epidermidis isolates from Emory Hospital 1980-1986) and sensitive to gentamicin. Four cases of S. epidermidis occurred in patients treated with gentamicin; all of these were resistant to gentamicin (P < 0.01) and sensitive to chloramphenicol. Although no pseudomonas ulcers developed in the gentamicin group, two were seen in the chloramphenicol group. No pseudomonas ulcers developed in the 12 eyes wearing contact lenses for refractive purposes. Culture of lens solutions

::J U

cr:

III ::J

II)

:> c

0 ;:

.. U

Q)

c

.:. II)

0 Cl.

Total

73 32 3

0 0 1

15 0

2 24

~

Unknown

23

12 10

STATISTICAL DIFFERENCES AMONG SUBGROUPS

1454

Emergency Regraft

No Regraft

38

20/20 20/25 20/30 20/40 20/50 20/60 20/70 20/80 20/100 20/200 20/300 20/400 CF HM LP NLP

108

•

•• •

.0

0

• 0

•

0

• 0 0

•

0

O.

0

0

• o e.00

80

Pre-Infection Visual Acuity Fig 4. Visual acuity before keratitis and at most recent follow-up in 67 eyes followed at least 6 months after initial keratitis episode. Closed circles represent eyes in which the first episode of keratitis occurred less than IO months after penetrating keratoplasty. Open circles represent eyes with more delayed keratitis.

was not possible in the 30 ulcers associated with extended wear contact lenses, because sterilization of therapeutic and aphakic lenses was performed in the clinic at previous visits. Of the remaining three contact lens wearers, all of whom were keratoconus patients with gas-permeable rigid contact lenses, cultures of lens solutions and cases were recorded as positive in only one case. Serratia mareeseens was recovered from the lens case, wetting solution, and cornea in this patient. Overall, the spectrum of infecting organisms in patients wearing contact lenses was similar to that of the series as a whole, with C. alMeans and S. epidermidis predominating. Of the three most commonly used antibiotics, the bacitracin polymyxin combination was most closely associated with C. albieans. with 16 (62%) of 26 eyes growing this organism (P < 0.001). C. albieans was isolated in 45 and 29% of cases under treatment with chloramphenicol and gentamicin, respectively. Fungal ulcers occurred in only 1 (3%) of 32 eyes not using antibiotics (P < 0.001)

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and in 1 (9%) of 11 patients not using corticosteroids (P = 0.10). Several trends were noted among cases grouped by microorganism. Although both fungi and bacteria were commonly seen among 58 eyes with clear anterior chambers or moderate cellular reactions, only 1 of 34 pure fungal infections caused a hypopyon (P < 0.01). C. albieans was associated with a frequent need for emergency regraft (14 of 27 cases, or 52%; P = 0.06); only 4 (20%) of 20 previously clear grafts remained clear after C. albieans infection. S. epidermidis infections occurred predominantly during warm weather, with 72% of cases occurring between May and August. Streptococcal infections were associated with exposed sutures in seven (78%) of nine cases (P < 0.005). S. mareeseens produced a relatively benign infection with six (85%) of seven grafts remaining clear (P = 0.03). Pseudomonas aeruginosa ulcers carried a uniformly poor prognosis, with no clear grafts resulting among seven cases (P = 0.20). Median final visual acuity in these cases was light perception (P = 0.08). Five of ten eyes that yielded mUltiple pathogens from a single ulcer eventually lost light perception (P < 0.005). Eyes with repeated infections and eyes that required emergency regraft fared poorer than average, with median final visual acuity of hand motions in each group. These differences were not statistically significant (P = 0.20 and 0.12, respectively). Fifteen (52%) of 29 noninitial ulcers grew organisms seen in previous keratitis. Eight of these involved C. albieans. S. mareeseens was recovered from a corticosteroid dropper bottle used by one patient after he presented with a second infection caused by this organism.

DISCUSSION REVIEW OF THE LITERATURE

Since many cases of graft infection are included in larger series of corneal ulcers, it is not possible to enumerate all such cases reported in the literature. However, the largest series was a group of 29 patients studied by Tuberville and Wood 1in 1981. Although they included three Gramand culture-negative cases, their subjects resembled ours with regard to the association of ulcers with loose sutures, therapeutic contact lenses, topical steroids and antibiotics, the presence of multiple pathogens, and the degree of visual loss. Staphylococci and streptococci were common pathogens in both studies with streptococci implicated in many exposed suture cases. However, no fungal ulcers were seen in their series, in striking contrast to a 36% incidence in ours. Interestingly, they saw no resistance to prophylactic antibiotics in six cases tested, as opposed to an 89% incidence in 56 cases in the current study. They found 90% of pathogens tested to be sensitive to gentamicin. We found gentamicin sensitivity in only 38% of our isolates. Ulcers developed earlier in their patients after penetrating keratoplasty (median, 5.5 versus 9 months), and their patients were more likely to have had herpetic ocular disease (32 versus 14%). Only 1 (4%) of 28 patients

in their series suffered repeat infection; we noted subsequent infection in 19 (24%) of 79 eyes. A sampling of other reported cases includes 13 seen in association with therapeutic contact lenses,2-4 11 in larger keratitis series,5,6 8 in eyes grafted for herpes simplex keratitis,7,8 6 cases in which infection lead to endophthalmitis in eyes that subsequently developed,9 6 related to extended-wear aphakic contact lenses,IO-13 4 as noninflammatory infectious crystalline keratopathy,14-16 2 caused by atypical mycobacteria,17-19 and 8 in miscellaneous reportS. 20- 25 Two of the previously reported cases are included in the current series. 19,24 Taken together, these cases are similar to ours, in that ordinarily nonpathogenic microorganisms were frequently implicated. However, the incidence of keratomycosis in our series was high in comparison to those previously reported graft infections, only 6% of which were fungal. C. albieans was isolated much more frequently in our study than in any previously reported series of corneal ulcers. For example, only 9 of 647 reported cases of infectious keratitis from New York were fungal, and only 5 of these were caused by C. albieans. 26 Similarly, C. albieans was implicated in 3 of 100 cases from Michigan and 2 of232 cases from Texas. 5,27 Even in southern Florida, where fungi caused 133 (36%) of371 culture-proven ulcers, C. albieans accounted for only 10 (3%) of the total. 28 The highest reported incidence of Candida keratitis among fungal ulcers was 40% (12 of30) in a series from San Francisco. 29 C. albieans, a common intestinal saprophyte, has easy access to the external eye and has been cultured from the conjunctivae of normal eyes. 30 Impaired cell-mediated immunity from corticosteroid therapy and alteration of normal flora by antibiotics probably render the external eye susceptible to Candida colonization, as is the case in mucocutaneous candidiasis. Gentamicin has been shown to inhibit human leukocytic phagocytosis of C. albieans in vitro (but not in vivo); however, its use was not significantly correlated with C. albieans ulcers in this series. 31 ,32 We suspect that the prolonged use of topical antibiotics and corticosteroids encourages C. albieans infection after corneal transplantation. Geographic variation, higher risk patients with poor ocular surface and immune function, or differences in the duration and types of topical therapy used by our patients, could account for the higher incidence of Candida infections in our series compared with previously reported transplant infections. S. epidermidis, the second most frequently isolated organism among our cases, was not even listed among corneal pathogens found in 3353 ulcers seen in New York between 1938 and 1968. 33 In recent years, however, S. epidermidis has been recognized with increasing frequency as an invader of the compromised cornea. 5,6,26,29 We saw a remarkable ability of this organism to modify its antibiotic resistance; all strains isolated from eyes treated prophylactically with gentamicin or chloramphenicol were resistant to the antibiotic used. ANTIBIOTICS

The high frequency (89%) of resistance to prophylactic antibiotics in this series contradicts the findings in most 1455

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other reports on chronic administration of topical antipiotics to the eye. In two 12-week studies using chloramphenicol in normal eyes and a neomycin/polymyxin/ gramicidin combination in eyes with soft contact lenses, Binder et al 34,35 found no significant antibiotic resistance, whereas Smith et all found resistance in three of six eyes wearing therapeutic contact lenses. The prolonged duration of antibiotic therapy in our patients may explain the higher frequency of resistance we found. Though in this uncontrolled study a risk !lssessment is not possible, our results <;ertainly call into question both the safety and the efficacy of chronic topical antibiotic administration in the postoperative eye or in the eye wearing a therapeutic contact lens. CONTACf LENSES

Controversy exists in the literature regarding the safety of therapeutic contact lenses after corneal transplantation. Paglen et al 36 and Aquavella and Shaw37 reported no infectious keratitis in 68 and 41 cases, respectively; however, Smith et al 3 found a 23% incidence in 47 eyes. These differences probably reflect the severity of disease for which lenses were prescribed. For example, Paglen et al routinely used lenses in penetrating keratoplasty patients because of their exposed knot technique, whereas most lenses used by Smith et al were prescribed for persistent epithelial defects. Keratitis associated with contact lens wear in the current study seemed to differ from that reported in the literature. For example, the absence of f~eudomonas ulcers in patients wearing extended-wear refractive lenses was in striking contrast to a 64% incidence seen in a recent large series of contact lens wearers, and a 75% incidence reported in cosmetic extended-wear contact lens patients. 38 ,39

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cans or P. aeruginosa, and need for emergency regraft. Those eyes grafted for keratoconus and those infected by S. marcescens had a better-than-average outcome. The interval between surgery and infection did not affect the final outcome. . POTENTIAL RISK FACfORS

Our cases and those in the literature demonstrate several common factors inherent in corneal transplantation and its postoperative management that render an eye susceptible to infectious keratitis and increase the severity of disease if infection occurs. Chronic antibiotic use may alter the population of organil'ms present on the con~ junctival surface and compromise the corneal epithelium by inducing toxic epitheliopathy.34,4o In the case of gentamicin, the host phagocytic response may be inhibited. 31 Corticosteroids impair host defense and healing mechanisms, reduce important symptoms and signs of infection such as pain and ciliary injection, and may increase the fungal component of the conjunctival flora. 40,41 Persistent epithelial defects, punctate keratopathy, exposed sutures, minor trauma from contact lenses, and recurrent herpetic disease disrupt the epithelial barrier to infection. Poor baseline visual acuity may impair the patient's ability to recognize mild visual loss in early stages of infection, thus delaying diagnosis and appropriate treatment. Finally, graft hypesthesia, present universally after corneal transplantation,42 may decrease symptoms and delay treatment. Subnormal corneal innervation may also induce abnormalities of epithelial mitosis, healing, and adhesion, though this has not been demonstrated conclusively in grafts. 42 These factors combine to allow destructive invasion of the graft by both common corneal pathogens, such as P. aeruginosa and S. aureus, and ordinarily saprophytic pathogens such as S. epidermidis and C. albicans.

GRAM STAIN

We were able to identify the causative organisms on Gram-stained scrapings in 73% of cases, with similar success rates for bacteria and fungi. This is in agreement with a success rate of 71 % previously reported by Jones. 27 Several characteristics of the p()pulation we studied might have increased the probability that a large number of organisms would be present at initial evaluation. These include low virulence of the infecting organism (more organisms are required to cause disease) and factors that delay presentation, including poor visual acuity, steroid treatment, and perhaps decreased corneal sensation. Application of broad-spectrum antibiotics by referring physicians before diagnostic studies would tend to decrease the chances of finding the causative organism on Gram stain or culture. PROGNOSTIC FACfORS

Our data indicate that infectious keratitis after penetrating keratoplasty is associated with a dismal outcome in most cases. Factors associated with a poor result included a diagnosis of herpes simplex keratitis, repeated infections, polymicrobial infection, infection by C. albi1456

CONCLUSIONS AND RECOMMENDATIONS Since penetrating keratoplasty now carries an excellent prognosis for graft clarity, late bacterial and fungal keratitis, constittf1:e a significant source of morbidity in corneal transplant patients. Because the common symptoms of infectious keratitis may be absent in keratoplasty patients, they should be advised to seek treatment immediately if they see a "white spot" on the operated eye or have any abnormality that persists for more than 24 hours. Treatment should be withheld until the cornea has been scraped for Gram stain and culture. If the patient is using topical corticosteroids and antibiotics chronically, C. albicans and S. epidermidis are likely offenders; otherwise, S. aureus, Pseudomonas sp, Serratia sp, S. pneumoniae, and Proteus sp may be suspected. The choice of initial antibacterial or antifungal therapy should be based on the Gram stain if definitive. Otherwise, drugs that cover a broad spectrum of bacterial pathogens should be used; empirical antifungal medication may also be indicated if the clinical situation suggests fungal etiology. Intensive therapy (e.g., I drop of

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LATE INFECTIONS IN CORNEAL TRANSPLANTS

fortified antibiotic every minute for 5 minutes followed by around-the-clock administration) is imperative. For certain patients, hospitalization may be required to ensure optimal treatment and monitoring, because of the significant risk for loss of graft clarity and vision in these compromised eyes. All topical medications in use before infection should be discarded. Our data suggest, but do !lot prove, that patients with a diagnosis of herpes simplex keratitis and those using topical steroids, antibiotics, or therapeutic bandage lenses are predisposed to late bacterial or fungal keratitis developing after penetrating keratoplasty. A controll~d study to determine risk factors is currently under way.

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