Necrotizing Keratitis Caused by Capnocytophaga ochracea

Necrotizing Keratitis Caused by Capnocytophaga ochracea D a v i d G. H e i d e m a n n , M . D . , S t e p h e n C. Pflugfelder, M . D . , Jan Kronish, M . D . , Eduardo C. A l f o n s o , M . D . , Steven P. D u n n , M . D . , and Saul U l l m a n , M . D . We studied three cases of Capnocytophaga keratitis that demonstrated stromal necrosis and a ring infiltrate. In all cases, the keratitis occurred in a previously diseased or traumatized cornea. One patient was treated with chronic antiamoebic therapy for presumed Acanthamoeba keratitis. Two cases resulted in corneal perforation. Laboratory isolation was difficult because of slow, fastidious growth. Capnocytophaga is not uniformly sensitive to commonly used topical antibiotics such as the cephalosporins and aminoglycosides, but may respond to treatment with topical clindamycin. CAPNOCYTOPHAGA (formerly Bacteroides och­ racea and Centers for Disease Control biogroup DF-1) is a gram-negative fusiformshaped bacterium, known for its gliding motility and capnophilic (CCvloving) metabolism. 1 3 Capnocytophaga is part of the normal human oral flora and is sometimes found in sputum and throat specimens. It is a frequent cause of periodontitis and has caused a variety of infec­ tions in immunocompromised and neutropenic patients. 4 9 Recently, Capnocytophaga has been found to cause infections in nonimmunocompromised patients. 10 Capnocytophaga con­ junctivitis and canaliculitis have been report­ ed. 1011 To our knowledge, only two cases of Capnocytophaga keratitis have been reported, both occurring in previously diseased or trau­ matized corneas. 12 We report three additional cases that emphasize the clinical features of

Accepted for publication March 31, 1988. From the Department of Ophthalmology, William Beaumont Hospital, Detroit, Michigan (Drs. Heidemann and Dunn); the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida (Drs. Pflugfelder, Kronish, and Alfonso); and the Department of Ophthalmology, Medical Center Clinic, Pensacola, Florida (Dr. Ullman). This study was presented in part at the Ocular Immunol­ ogy and Microbiology Group Meeting, Dallas, Texas, Nov. 7, 1987. Reprint requests to David G. Heidemann, M.D., 29829 Telegraph Rd., Suite 201, Southfield, MI 48034.

stromal ring infiltrate associated with a necro­ tizing keratitis, endothelial plaque, and poten­ tial for severe inflammatory response. This organism must be considered in cases of necrotizing keratitis, since laboratory isolation may be difficult and it is relatively resistant to conventional topical antimicrobial therapy.

Case Reports Casel A 30-year-old woman was struck in the right eye with a piece of paper in December 1986 and developed a corneal abrasion, which healed in two days with pressure patching. In March 1987 she noted recurrent pain and redness in her right eye and was treated with a three-week course of unknown topical antibiotics for ulcerative keratitis with no improvement. She was referred to the Bascom Palmer Eye Institute on April 8, 1987. Visual acuity in the right eye was hand motions. Slit-lamp examination demon­ strated a central epithelial defect with a ring stromal infiltrate (Fig. 1). A presumptive clini­ cal diagnosis of Acanthamoeba keratitis was made, and a corneal scraping and biopsy were performed. Gram, Giemsa, and calcofluor white stains were negative, and there was no growth on Escherichia coli overlaid nonnutrient blood agar. She was treated with topical 0.1% propamidine isethionate every hour, topical homatropine, paromomycin, 1% prednisolone phosphate, and clotrimazole cream four times a day, and 200 mg of ketoconazole by mouth daily. Eight days later, a second corneal biopsy was performed, but Gram, Giemsa, and calco­ fluor white stains as well as cultures on £. coli overlaid nonnutrient blood agar were negative for Acanthamoeba. The keratitis worsened, and a severe anterior chamber reaction developed. Cyanoacrylate tissue adhesive was placed on the temporal biopsy site on May 25, 1987, because of im­ pending perforation. On June 8, 1987, a mas­ sive necrotizing keratitis associated with a cor­ neal perforation at the inferior biopsy site was

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Fig. 1 (Heidemann and associates). Case 1. Central epithelial defect with double ring stromal infiltrate.

Fig. 2 (Heidemann and associates). Case 1. Necrotizing keratitis with corneal perforation at inferior biopsy site.

noted (Fig. 2). A 12-mm penetrating keratoplasty with stripping of inflammatory mem­ branes was performed on the same day. Histopathologic examination showed massive polymorphonuclear cell infiltration and necro­ sis, but no Acanthamoeba cysts, trophozoites, or other organisms. Postoperative treatment con­ sisted of hourly topical fortified cefazolin (50 mg/ml) and Neosporin, as well as oral ketoconazole (200 rrtg/day) and prednisone (60 mg/day). On June 12, 1987, C. ochracea was cultured from the corneal button on four differ­ ent media, including blood and chocolate agar under increased carbon dioxide tension, blood agar in an anaerobic jar, and thioglycolate broth. A persistent epithelial defect was pres­ ent postoperatively, and on July 1, 1987, a superior peripheral stromal ring infiltrate was noted. Corneal scrapings were performed and yielded no growth. The infiltrate and anterior chamber reaction increased, and on July 10, 1987, oral azathioprine (50 mg/day) was pre­ scribed for presumed allograft rejection. The clinical course worsened, and on July 15, 1987, a repeat 12-mm penetrating keratoplasty was performed. Postoperatively, the corneal epithe­ lium did not heal and a tarsorrhaphy was per­ formed. It was subsequently discovered that she had been frequently and regularly using topical tetracaine and proparacaine since her symptoms began in March 1987. All topical medications were stopped, and the epithelium healed within several weeks. Visual acuity in December 1987 was light perception with pro­ jection. The graft was edematous and an intumescent cataract was present.

Case 2 A 40-year-old man was splashed in his left eye with an organic solvent used for stripping paint on June 22, 1986. His eyes were immedi­ ately irrigated with water and he was referred to the Bascom Palmer Eye Institute. Visual acuity was 20/400 in the left eye, with moderate conjunctival injection and a large central epi­ thelial defect. There was a mild anterior cham­ ber reaction. Treatment consisted of pressure patching, bacitracin zinc-polymyxin B sulfate ointment, and 5% homatropine eyedrops two times daily. After initial improvement, a total epithelial defect developed with diffuse stro­ mal edema, Descemet's folds, and moderate anterior chamber reaction. Treatment was changed to topical tobramycin (3 mg/ml), 1% prednisolone acetate, and 1% cyclopentolate four times daily. The epithelium began to heal, but on July 1, 1986, a peripheral stromal ring infiltrate with a large central endothelial plaque developed. The patient was treated with 80 mg of prednisone by mouth daily. Results of B-scan ultrasonography of the posterior seg­ ment were normal. On July 9, 1986, the anterior chamber reaction increased and a 60% hypopyon was present (Fig. 3). Corneal scrapings were performed for smears and cultures. Gram and Giemsa stains demonstrated inflammatory cells but no organisms. On July 11, 1986, a corneal biopsy and anterior chamber lavage were per­ formed. Peripheral corneal thinning developed and cyanoacrylate tissue adhesive was placed because of peripheral corneal thinning and im­ pending perforation. By July 15, 1986, cultures of both the corneal scraping and biopsy yielded

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Fig. 3 (Heidemann and associates). Case 2. Ring infiltrate, endothelial plaque, and 60% hypopyon.

Fig. 4 (Heidemann and associates). Case 2. Mas­ sive stromal necrosis and corneal perforation.

growth of C. ochracea on blood agar in the anaerobic jar, sensitive to clindamycin and penicillin. Treatment was initiated with topical fortified penicillin (100,000 units/ml) and clin­ damycin (50 mg/ml) every 30 minutes. On July 19, 1986, cyanoacrylate tissue adhesive was applied to the superior peripheral cornea be­ cause of impending perforation. On July 25, 1986, diffuse stromal necrosis and a central corneal perforation plugged with necrotic de­ bris was noted (Fig. 4). On the same day, a 12-mm penetrating keratoplasty, anterior chamber membranectomy, synechialysis, and iridectomy were performed. Histopathologic examination showed diffuse polymorphonuclear cell infiltration and necrosis, but no or­ ganisms. Cultures of the corneal button were negative. The postoperative course was marked by an intense anterior chamber inflam­ matory reaction. On Oct. 19, 1986, an edematous cornea and flat anterior chamber secon­ dary to an intumescent lens were noted. The next day, a lens aspiration, anterior chamber membranectomy, and synechialysis were per­ formed. Three months postoperatively, the pa­ tient had diffuse corneal edema, normal intra­ ocular pressure, and a visual acuity of light perception.

250 mg of oral tetracycline four times daily, and pressure patching. On Sept. 22, 1987, a ban­ dage contact lens was placed because of a nonhealing epithelial defect. Six days later, slit-lamp examination disclosed a large central epithelial defect, with a partial stromal ring infiltrate, and an area of stromal necrosis, with approximately 25% thinning (Fig. 5). Visualiza­ tion of the anterior chamber was difficult. Cor­ neal scrapings were performed, and treatment with hourly topical cefazolin (50 mg/ml) and tobramycin (14 mg/ml) was initiated. Three days later, cultures of both cornea and contact lens yielded growth of a gram-negative rod on chocolate and blood agar incubated under in­ creased carbon dioxide tension. The organism was sensitive to cefazolin, but resistant to to-

Case 3 An 83-year-old woman with a 20-year history of open-angle glaucoma had bilateral band keratopathy and a visual acuity of hand motions in the right eye. On Aug. 20, 1987, she underwent a superficial keratectomy in the right eye. She was treated with topical tobramycin (3 mg/ml) and 1% prednisolone acetate four times daily,

Fig. 5 (Heidemann and associates). Case 3. Central epithelial defect with stromal necrosis and partial ring infiltrate.

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bramycin and gentamicin. The organism was later identified as C. ochracea by the Michigan Department of Public Health. The patient re­ sponded slowly to treatment with topical cefazolin (50 mg/ml). On Oct. 28, 1987, visual acuity was light perception and slit-lamp exam­ ination showed one pinpoint area of fluorescein stain, resolution of the infiltrate, superficial vascularization, and minimal anterior chamber reaction.

Discussion Capnocytophaga is a dysgonic fermenter, and produces a yellow pigment on solid media. DNA base homology, biochemistry, and mor­ phologic studies have yielded three species: C. ochracea, C. sputigena, and C. gingivalis.13'16 Capnocytophaga ochracea was formerly known as Fusobacterium nucleatum var. ochraceus, Ristella ochracea, and Bacteroides oralis var. elongatus.2 It was later identified as Bacteroides ochraceus or Centers for Disease Control biogroup DF-1. The taxonomy was rather confus­ ing until recently, when two independent re­ ports established that B. ochracea, Centers for Disease Control biogroup DF-1, and Capnocyto­ phaga were synonymous. 1,2 The two previously described patients with Capnocytophaga keratitis exhibited similar clini­ cal features to our three patients (Table).12 These two cases plus our three cases all oc­ curred in previously diseased or traumatized

corneas. In our three cases, each patient was receiving topical corticosteroids. Patient 1 was also receiving topical anesthetics and chronic antiamoebic therapy, which may have further predisposed her to infection. Secondary bacter­ ial infectious keratitis developing during the treatment of Acanthamoeba keratitis has previ­ ously been reported. 1719 In the five total cases, four patients had a peripheral stromal ring infiltrate, four patients had an inflammatory endothelial plaque, and two patients developed a severe anterior cham­ ber inflammatory reaction and corneal perfora­ tion. Capnocytophaga produces various patho­ genic factors leading to complex interactions with host defenses. Capnocytophaga ochracea produces a protease that can degrade IgA-1 and polyclonal IgG, which may decrease local de­ fenses and contribute to pathogenicity. 20 Capno­ cytophaga ochracea produces a heat-stable, dialyzable substance that alters local neutrophil migration and morphology, 21 but it did not prevent massive neutrophil infiltration in our Patients 1 and 2. This neutrophil infiltration may have been caused by endotoxin-mediated alternate pathway complement fixation. All three species of Capnocytophaga produce an endotoxin. 20 Many Capnocytophaga infections occur in patients who are neutropenic or have hematologic malignancies. 4 " 1021 Patient 1 had a persistently increased white blood cell count of greater than 20,000/mm3, but refused to under­ go a bone marrow biopsy. Clinically, a necrotizing keratitis with stro­ mal ring infiltrate may suggest several diagnos-

TABLE CLINICAL FEATURES OF CAPNOCYTOPHAGA KERATITIS AGE

STROMAL RING

(YRS),

INVESTIGATORS

SEX

HISTORY

DIAGNOSTIC METHOD

INFILTRATE AND NECROSIS

TOPICAL TREATMENT AND OUTCOME

43, F

Corneal edema

Corneal scraping

No

Clindamycin; healed

35, M

Blunt trauma

Corneal scraping

Yes

Clindamycin; healed

30, F

Anesthetic abuse

Corneal button

Yes

Case 2

40, M

Chemical injury

Corneal scraping and biopsy

Yes

Case 3

83, F

Epithelial debridement

Corneal scraping and contact lens

Yes

Propamidine, clotrimazole, paromomycin; perforation; penetrating keratoplasty x2; failed Penicillin, clindamycin; perforation; penetrating keratoplasty; failed Cefazolin, tobramycin; healed

Roussel, Osalo, and Wilhelmus Roussel, Osato, and Wilhelmus Present study Case 1

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tic possibilities, including Acanthamoeba, her­ pes simplex, anesthetic abuse, as well as Pseudomonas, Proteus, or other endotoxinproducing gram-negative bacteria. In our three patients, the infiltrate was initially dry and did not have the typical appearance of suppurative keratitis caused by a gram-negative organism such as Pseudomonas. All three patients, howev­ er, later developed massive necrotizing kerati­ tis. The history of a previously diseased or compromised cornea, the clinical appearance, and the slow, insidious onset with relentless progression may be especially suggestive of AcaKithamoeba keratitis. Patient 1 was treated for presumed Acanthamoeba keratitis, but culture and stain of two corneal biopsy specimens and the corneal button did not confirm this diagno­ sis. The ring infiltrate may have been caused by chronic anesthetic abuse and it is not known if Capnocytophaga caused a primary or secondary infection. Isolation of Capnocytophaga is difficult and the diagnosis may be missed if proper culture tech­ nique is not used. Capnocytophaga is a faculta­ tive anaerobe and requires a CCVenriched at­ mosphere for growth. It may grow on CCVenriched blood or chocolate agar or may grow only on anaerobic media. 5 In Case 1, results of early corneal scrapings and biopsy specimens were negative, but were performed while the patient was receiving topical antibiot­ ics. Later, cultures of the corneal button grew Capnocytophaga on C0 2 -enriched blood and chocolate agar, blood agar in the anaerobic jar, and thioglycolate broth. In Case 2, cultures of the corneal scrapings and biopsy specimen grew Capnocytophaga in anaerobic media only. In Case 3, cultures of corneal scrapings and the contact lens grew Capnocytophaga on C0 2 -enriched blood and chocolate agar. In all three cases, growth was not noted until three or more days after inoculation. Capnocytophaga is a fas­ tidious organism, and even when proper cul­ ture media and technique are used, isolation may be difficult because of slow growth or overgrowth by other organisms in uncommon instances of mixed infections or contaminated specimens. 1 This emphasizes the importance of routinely stopping antibiotics before cultures, using media incubated in increased carbon di­ oxide tension and anaerobic conditions, and holding cultures for greater than three days when evaluating infectious keratitis. If cultures are negative and the clinical course worsens, corneal biopsy should be considered. Capnocytophaga is sensitive to antimicrobial agents that have the greatest activity against

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anaerobes. In vitro sensitivity testing of Capno­ cytophaga has demonstrated sensitivity to clindamycin, penicillin, chloramphenicol, tetracycline, and carbenicillin, with relative resistance to aminoglycosides, polymyxins, and vancomycin. Sensitivity to the cephalosporins is vari­ able.22,23 Recently, beta-lactamase-producing strains have been reported. 24 Both patients de­ scribed by Roussel, Osato, and Wilhelmus 12 did not respond to initial therapy with topical and subconjunctival cefazolin or gentamicin, but healed with topical and subconjunctival clindamycin. Of our cases, one patient (Patient 3) healed slowly with topical cefazolin. The other two patients developed a severe necrotizing keratitis, resulting in corneal perforation. One patient (Patient 2) did not respond to appropri­ ate topical therapy with penicillin and clindamycin, but the diagnosis was made late in the clinical course. The cornea of the other patient (Patient 1) perforated while the patient was receiving long-term antiamoebic therapy. Based on these cases as well as in vitro sensitiv­ ity testing, topical clindamycin may be the most effective treatment for Capnocytophaga ker­ atitis.

References 1. Newman, M. G., Sutter, V. L., Pickett, M. J., Blachman, U., Greenwood, J. R., Grinenko, V., and Citron, D.: Detection, identification and comparison of Capnocytophaga, Bacteroides ochraceus, and DF-1. J. Clin. Microbiol. 10:557, 1979. 2. Williams, B. L., Hollis, D., and Holdeman, L. V.: Synynomy of strains of Centers of Disease Control Group DF-1 with species of Capnocytophaga. J. Clin. Microbiol. 10:550, 1979. 3. Holdeman, L. V., Cato, E. P., and Moore, W. E. C : Taxonomy of anaerobes. Present state of the art. Rev. Infect. Dis. 6:3, 1984. 4. Warren, J. S., and Allen, S. D.: Clinical, pathogenetic, and laboratory features of Capnocytophaga infections. Am. J. Clin. Pathol. 86:513, 1986. 5. Hawkey, P. M., Malnick, H., Glover, S. A. M., Cook, N., and Watts, J. A.: Capnocytophaga ochracea infection. Two cases and a review of the published work. J. Clin. Pathol. 37:1066, 1984. 6. Forlenza, S. W., Newman, M. A., Lipsey, A. I., Siegel, S. E., and Blachman, U.: Capnocytophaga sep­ sis. A newly recognized clinical entity in granulocytopenic patients. Lancet 1:567, 1980. 7. Gilligan, P. H., McCarthy, L. R., and Bissett, B. K.: Capnocytophaga ochracea septicemia. J. Clin. Microbiol. 13:643, 1981. 8. Haulk, A. A., Sugar, A. M., and Rushing, J. L.: Capnocytophaga septicemia. N. Engl. J. Med. 302:922, 1980.

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9. Shlaes, D. M., Dul, M. J., and Lerner, P. I.: Capnocytophaga bacteremia in the compromised host. Am. J. Clin. Pathol. 77:359, 1982. 10. Parenti, D. M., and Snydman, D. R.: Capno­ cytophaga species. Infections in nonimmunocompromised and immunocompromised hosts. J. Infect. Dis. 151:140, 1985. 11. Jones, D. B., and Robinson, N. M.: Anaerobic ocular infections. Trans. Am. Acad. Ophthalmol. Otolaryngol. 83:309, 1977. 12. Roussel, T. J., Osato, M. S., and Wilhelmus, K. R.: Capnocytophaga keratitis. Br. J. Ophthalmol. 69:187, 1985. 13. Leadbetter, E. R., Holt, S. C , and Socransky, S. S.: Capnocytophaga. New genus of gram-negative gliding bacteria. I. General characteristics, taxonomic considerations and significance. Arch. Microbiol. 122:9, 1979. 14. Holt, S. C , Leadbetter, E. R., and Socransky, S. S.: Capnocytophaga. New genus of gram-negative gliding bacteria. II. Morphology and ultrastructure. Arch. Microbiol. 122:17, 1979. 15. Socransky, S. S., Holt, S. C , Leadbetter, E. R., Tanner, A. C. R., Savitt, E., and Hammond, B. F.: Capnocytophaga. New genus of gram-negative gliding bacteria. III. Physiological characterization. Arch. Microbiol. 122:29, 1979. 16. Williams, B. L., and Hammond, B. F.: Capno­ cytophaga. New genus of gram-negative gliding bac­ teria. IV. DNA base composition and sequence homology. Arch. Microbiol. 122:35, 1979. 17. Cohen, E. J., Parlato, C. J., Arentsen, J. J.,

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Genvert, G. I., Eagle, R. C , Jr., Wieland, M. R., and Laibson, P. R.: Medical and surgical treatment of Acanthamoeba keratitis. Am. J. Ophthalmol. 103:615, 1987. 18. Mathers, W., Stevens, G., Jr., Rodrigues, M., Chan, C. C , Gold, J., Visvesvara, G. S., Lemp, M. A., and Zimmerman, L. E.: Immunopathology and electron microscopy of Acanthamoeba keratitis. Am. J. Ophthalmol. 103:626, 1987. 19. Davis, R. M., Schroeder, R. P., Rowsey, J. J., Jensen, H. G., and Tripathi, R. C : Acanthamoeba ker­ atitis and infectious crystalline keratopathy. Arch. Ophthalmol. 105:1524, 1987. 20. Fumarola, D., and Miragliotta, G.: Virulence factors of Capnocytophaga. Newer contributions. h.m. J. Clin. Pathol. 73:425, 1982. 21. Shurin, S. B., Socransky, S. S., Sweeney, E., and Stossel, T. P.: A rieutrophil disorder induced by Capnocytophaga, a dental micro-organism. N. Engl. J. Med. 301:849, 1979. 22. Forlenza, S. W., Newman, M. G., Horikoshi, A. L., and Blachman, U.: Antimicrobial susceptibili­ ty of Capnocytophaga. Antimicrob. Agents Chemother. 19:144, 1981. 23. Sutter, V. L., Pyeatt, D., and Kwok, Y. Y.: In vitro susceptibility of Capnocytophaga strains to 18 anti-microbial agents. Antimicrob. Agents Chemother. 20:270, 1981. 24. Arlet, G., Sanson-LePors, M. J., Castaigne, S., and Perol, Y.: Isolation of a strain of beta-lactamaseproducing Capnocytophaga ochracea. J. Infect. Dis. 155:1346, 1987.

O P H T H A L M I C MINIATURE

It is only a vision of what is Not Possible, for there is only reality, and man is reality, and what is seen and felt and smelled and tasted and heard with our senses is the only objectivity, and only truth. We are too Advanced for myths; we have achieved maturity and wisdom and intellect. Begone with Myths! Taylor Caldwell, Dialogues With The Devil New York, Fawcett World Library, 1967, p. 14