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Ciprofloxacin-resistant Bacterial Keratitis
Ciprofloxacin-resistant Bacterial Keratitis Michael E. Snyder, M.D., and Harold R. Katz, M.D.
Ciprofloxacin, a new broad-spectrum antibiotic effective against a variety of gram-positive and gram-negative bacteria, has recently become available in topical ophthalmic solution (3 mg/ml) for the treatment of bacterial keratitis. It has rapidly become the drug of choice in treating bacterial keratitis. We treated three patients with bacterial corneal ulcers that were resistant to ciprofloxacin, yet were effectively treated with other topical antimicrobial agents. The initial culture results are important in the therapy of corneal ulcers. i^iPROFLOXACiN is the most active of the new class of fluorinated quinolone antibiotics. 1 It has recently become commercially available in a 0.3% ophthalmic solution. Because ciproflox acin is a single, readily available broad-spec trum antibiotic active against both grampositive and gram-negative organisms, it is becoming a first-choice drug in the treatment of bacterial corneal ulcers. Within the last five months, we treated three patients with bacteri al keratitis at the Krieger Eye Institute in whom ciprofloxacin therapy failed and who were cul ture positive for ciprofloxacin-resistant organ isms. Two patients were treated with ciprofloxa cin solution (Ciloxan, Alcon Laboratories, Fort Worth, Texas), whereas the third patient was treated initially with ciprofloxacin 0.3% oph thalmic ointment as part of an ongoing study with Alcon Laboratories. All three patients were successfully treated with conventional fortified antibiotics.
Accepted for publication June 11, 1992. From the Krieger Eye Institute, Sinai Hospital of Balti more (Drs. Snyder and Katz), a n d Wilmer O p h t h a l m o logical Institute, Johns Hopkins Hospital (Dr. Katz), Baltimore, Maryland. Reprint requests to Harold R. Katz, M.D., Krieger Eye Institute, Department of Ophthalmology, Sinai Hospital of Baltimore, Belvedere at Greenspring, Baltimore, MD 21215-5271.
336
Case Reports Case 1 A 67-year-old man underwentbilateral uppereyelid levator aponeurosis repair for blepharoptosis. On postoperative day 1, he had severe conjunctival chemosis with conjunctival pro lapse that prevented closure of his eyelids. Despite an aggressive treatment regimen of hourly lubrication with ointment, the patient's corneal epithelium appeared to be irregular on the next day, though no staining defects were noted. Tobramycin 0.3% ointment was added four times daily for prophylaxis, which the patient used only once because of discomfort. The next day he had three small areas of inferi or paralimbal moderately dense corneal stromal infiltrates with overlying epithelial defects. Corneal scrapings and cultures were performed and the patient was given ciprofloxacin 0.3% ophthalmic solution hourly. One day later, the infiltrate worsened and 24-hour culture results disclosed methicillin-sensitive Staphylococcus epidermidis resistant to ciprofloxacin and sensi tive to cefazolin (Table). The patient's treat ment was switched to topical cefazolin 50 m g / ml, hourly, and the infiltrate resolved and the corneal epithelium healed within the next three weeks. Case 2 A 63-year-old woman with a central corneal ulcer was referred to the Krieger Eye Institute. The patient had undergone previous uncompli cated extracapsular cataract extraction for a mature cataract several years earlier. Her post operative visual acuity was counting fingers because of diabetic retinopathy. Examination disclosed a dense stromal infiltrate with an overlying epithelial defect. Cultures and scrap ings of the ulcer were performed. The patient was treated with ciprofloxacin 0.3% ointment every two hours according to the protocol in an ongoing investigation with Alcon Laboratories on the safety and efficacy of ciprofloxacin oint-
© A M E R I C A N JOURNAL OF OPHTHALMOLOGY 114:336-338, SEPTEMBER, 1992
Ciprofloxacin-resistant Bacterial Keratitis
Vol. 114, No. 3
TABLE SENSITIVITIES TO ORGANISMS CULTURED FROM BACTERIAL KERATITIS* STAPHYLOCOCCUS
XANTHOMONAS
EPIDERMIS
MALTOPHILA
MIC-90 (MG/ML)
MICeo (MS/ML)
ANTIBIOTIC
CASE1
CASE 2
CASE 3
Amikacin Cefazolin Ceftazidime Ceftriaxone Chloramphenicol Ciprofloxacin Clindamyoin Gentamlcln Oxacillin Penicillin Ticarcillin Tobramycin Vancomycin
—
—
>32R
£1 S
4R
— —
— —
> 16 R >2R < 0.12 S >8R <0.5S >8R
8S >2R 0.25 S >8R >6R >8R
—
— —
4S 2S
2S
— 8S >32R
— >2R
— > 8R
— — 8S > 8 R
—
*S denotes sensitive; R denotes resistant; a dash indicates not tested.
ment in the treatment of bacterial keratitis. In the protocol of that study, patients are treated with ciprofloxacin ointment every two hours for the first 48 hours, and then every four hours at the discretion of the investigator. The corneal infiltrate improved on the first and second days after initiation of therapy and ciprofloxacin crystals were present on the stromal surface. The 48-hour culture results disclosed coagulase-negative S. epidermidis that was resistant to both cefazolin and ciprofloxacin, and that was sensitive to vancomycin (Table). Because of the initial favorable response to ciprofloxacin, the treatment with ciprofloxacin ointment was continued for 12 days. When the corneal infil trate failed to improve further, the patient's treatment was switched to topical vancomycin solution (50 mg/ml) every hour with a subse quent taper regimen. The patient's infiltrate cleared and the corneal epithelium healed with in the next 12 days. Case 3 A 53-year-old woman with a visual acuity of no light perception in the left eye because of uveitic glaucoma had a one-week history of pain and discharge from her blind left eye. Examina tion of the right eye disclosed a visual acuity of
337
20/25, a small hypopyon, and a mild vitreitis with perivenous sheathing of the retinal ves sels. Examination of the left eye disclosed mod erate conjunctival injection, moderate dis charge, a 4 x 5-mm dense central stromal infiltrate with an overlying epithelial defect, and a 2-mm hypopyon. Her medications at that time were timolol 0.5% instilled in the left eye twice daily and prednisolone acetate 1% ap plied to the left eye twice daily. Corneal scrap ings and cultures were performed, and the pa tient was treated hourly with ciprofloxacin 0.3% ophthalmic solution, three times a day with atropine sulfate 1% to both eyes, and twice a day with 40 mg of prednisone. Bacterial corneal ulcer in the left eye and Behçet's dis ease were diagnosed. The patient's corneal in filtrate did not improve over the next two days. The 48-hour culture results disclosed Xanthomonas maltophila resistant to ciprofloxacin and sensitive to ticarcillin (Table). When therapy was changed to hourly ticarcillin drops (4.1 mg/ml), the patient showed rapid initial im provement followed by gradual improvement over three weeks, but subsequently the epithe lium failed to heal and progressed to perfora tion.
Discussion The fluorinated quinolone antibiotics were first introduced for the treatment of systemic infections in the late 1980s. 1 Their use rapidly increased for the treatment of many systemic infections varying in severity from severe lifethreatening infections to fairly minor infec tions, such as uncomplicated urinary tract in fections. Initial experience with ciprofloxacin was positive and, although it remains a useful antibiotic for many severe infections, several resistant organisms have been detected. 24 The quinolones have more recently been in troduced to ophthalmology and appear to be effective in the treatment of corneal ulcers. Experimental animal studies 5,6 and more recent clinical trials 7 have shown that ciprofloxacin is an effective agent for infectious keratitis caused by a variety of organisms including methicillinresistant Staphylococcus species. It also appears to be effective in the treatment of experimental endophthalmitis (unpublished data from our laboratory, 1991). Ciprofloxacin offers the advantages of com-
338
September, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
mereiai availability, use as a single b r o a d - s p e c t r u m a g e n t , a n d g r e a t e r p o t e n c y in c o m p a r i s o n to other commercially available a n t i b i o t i c s . Leibowitz 7 found a n overall clinical success in 9 1 . 9 % of 148 corneal ulcers t r e a t e d w i t h c i p r o floxacin. Insler a n d associates 8 r e v i e w e d t w o cases of m e t h i c i l l i n - r e s i s t a n t S. aureus keratitis that were m a n a g e d successfully w i t h ciproflox acin. Ciprofloxacin h a s r a p i d l y b e c o m e t h e d r u g of choice in microbial keratitis for m a n y clinicians a n d is the only Food a n d D r u g A d m i n i s t r a t i o n - a p p r o v e d t r e a t m e n t for bacterial keratitis. Unlike a commercially p r e p a r e d eyed r o p , the p o t e n t i a l c o m p l i c a t i o n s of fortified p h a r m a c y - p r e p a r e d s o l u t i o n s are well k n o w n , s u c h as epithelial toxicity, p H v a r i a t i o n of t h e s o l u t i o n s , a n d c o n t a m i n a t i o n w i t h v i r u l e n t or ganisms. 8 1 1 The variable shelf life of h o s p i t a l p h a r m a c y - p r e p a r e d s o l u t i o n s also m a y limit the effectiveness of therapy. 1 2 1 3 At our i n s t i t u t i o n we have b e e n u s i n g cipro floxacin to treat p a t i e n t s w i t h bacterial keratitis since August 1989, a n d it h a s b e e n o u r d r u g of choice since it b e c a m e c o m m e r c i a l l y available. Overall, our r e s u l t s w i t h ciprofloxacin have b e e n excellent'; h o w e v e r , t h e t h r e e cases of this s t u d y d e m o n s t r a t e t h a t ciprofloxacin-resistant o r g a n i s m s exist. A l t h o u g h satisfactory r e s u l t s may occasionally be achieved w i t h a n t i b i o t i c s to w h i c h the c u l t u r e d o r g a n i s m s s h o w in v i t r o resistance, 1 0 the p o o r clinical r e s p o n s e in o u r cases was in a c c o r d a n c e w i t h the in vitro resist a n c e of the c u l t u r e d o r g a n i s m . A l s o , after t r e a t ment with antimicrobial agents that displayed in vitro activity to the c u l t u r e d o r g a n i s m , clini cal i m p r o v e m e n t w a s r a p i d . We a t t r i b u t e t h e u l t i m a t e failure of t r e a t m e n t in C a s e 2 to t h e h i g h - d o s e oral corticosteroid t r e a t m e n t t h a t was r e q u i r e d to treat the c o n t r a l a t e r a l eye (right eye) a d e q u a t e l y , w h i c h r e t a i n e d useful v i s i o n . A l t h o u g h ciprofloxacin a p p e a r s to b e a n ex cellent b r o a d - s p e c t r u m a n t i b i o t i c t h a t can be u s e d as the initial t h e r a p y in bacterial k e r a t i t i s , initial c u l t u r e s are vital in t h e t r e a t m e n t of bacterial corneal ulcers a n d a n t i m i c r o b i a l a g e n t s may n e e d to b e modified in specific cases d e p e n d i n g o n the clinical r e s p o n s e a n d t h e antibiotic sensitivities of the b a c t e r i a c u l t u r e d .
References 1. Neu, H. C : Microbiologie aspects of fluoroquinolones. Am. J. Ophthalmol. 112(suppl.):15S, 1991. 2. Raviglione, M. C , Boyle, J. F., Mariuz, P., Pablos-Mendez, A., Cortes, H., and Merlo, A.: Ciproflox acin-resistant methicillin-resistant Staphylococcus aureus in an acute-care hospital. Antimicrob. Agents Chemother. 34:2050, 1990. 3. Daum, T. E., Schaberg, D. R., Terpenning, M. S., Sottile, W. S., and Kaufman, C. A.: Increasing resistance of Staphylococcus aureus to ciprofloxacin. Antimicrob. Agents Chemother. 34:1862, 1990. 4. Fisher, L. M., Lawrence, J. M., Josty, I. C , Hopewell, R., Margerrison, E. E., and Cullen, M. E.: Ciprofloxacin and the fluoroquinolones. New con cepts on the mechanism of action and resistance. Am. J. Med. 87:2S, 1989. 5. O'Brien, I. P., Sawush, M. R., Dick, J. D., and Gottsch, J. D.: Topical ciprofloxacin treatment of Pseudomonas keratitis in rabbits. Arch. Ophthalmol. 106:1444, 1988. 6. Reiddy, J. J., Hobden, J. A., Hill, J. M., Forman, K., and O'Callaghan, R. J.: The efficacy of topical ciprofloxacin and norfloxacin in the treatment of experimental Pseudomonas keratitis. Cornea 10:25, 1991. 7. Leibowitz, H. M.: Clinical evaluation of cipro floxacin 0.3% ophthalmic solution for treatment of bacterialkeratitis.Am.J.Ophthalmol.ll2(suppl.):34S, 1991. 8. Insler, M. S., Fish, L. A., Silbernagel, J., Hob den, J. A., O'Callaghan, R. J., and Hill, J. M.: Suc cessful treatment of methicillin resistant Staphylococcus aureus keratitis with topical ciprofloxacin. Ophthalmology 98:1690, 1991. 9. Petroutsos, G., Guimaraes, Y., and Pouliquen, Y.: The effect of concentrated antibiotics on the rabbit's corneal epithelium. Int. Ophthalmol. 7:65, 1984. 10. Jones, D. B.: Decision-making in the manage ment of microbial keratitis. Ophthalmology 88:815, 1981. 11. Olsen, R. J.: How exposed are we? Arch. Oph thalmol. 107:1131, 1989. 12. Bowe, B. E., Snyder, J. W., and Eiferman, R. A.: An in vitro study of the potency and stability of fortified ophthalmic antibiotic preparations. Am. J. Ophthalmol. 111:686, 1991. 13. Osborne, E., Baum, J. L., Ernst, C , and Koch, P.: The stability of ten antibiotics in artificial tear solutions. Am. J. Ophthalmol. 82:775, 1976.
Ciprofloxacin, a new broad-spectrum antibiotic effective against a variety of gram-positive and gram-negative bacteria, has recently become available in topical ophthalmic solution (3 mg/ml) for the treatment of bacterial keratitis. It has rapidly become the drug of choice in treating bacterial keratitis. We treated three patients with bacterial corneal ulcers that were resistant to ciprofloxacin, yet were effectively treated with other topical antimicrobial agents. The initial culture results are important in the therapy of corneal ulcers. i^iPROFLOXACiN is the most active of the new class of fluorinated quinolone antibiotics. 1 It has recently become commercially available in a 0.3% ophthalmic solution. Because ciproflox acin is a single, readily available broad-spec trum antibiotic active against both grampositive and gram-negative organisms, it is becoming a first-choice drug in the treatment of bacterial corneal ulcers. Within the last five months, we treated three patients with bacteri al keratitis at the Krieger Eye Institute in whom ciprofloxacin therapy failed and who were cul ture positive for ciprofloxacin-resistant organ isms. Two patients were treated with ciprofloxa cin solution (Ciloxan, Alcon Laboratories, Fort Worth, Texas), whereas the third patient was treated initially with ciprofloxacin 0.3% oph thalmic ointment as part of an ongoing study with Alcon Laboratories. All three patients were successfully treated with conventional fortified antibiotics.
Accepted for publication June 11, 1992. From the Krieger Eye Institute, Sinai Hospital of Balti more (Drs. Snyder and Katz), a n d Wilmer O p h t h a l m o logical Institute, Johns Hopkins Hospital (Dr. Katz), Baltimore, Maryland. Reprint requests to Harold R. Katz, M.D., Krieger Eye Institute, Department of Ophthalmology, Sinai Hospital of Baltimore, Belvedere at Greenspring, Baltimore, MD 21215-5271.
336
Case Reports Case 1 A 67-year-old man underwentbilateral uppereyelid levator aponeurosis repair for blepharoptosis. On postoperative day 1, he had severe conjunctival chemosis with conjunctival pro lapse that prevented closure of his eyelids. Despite an aggressive treatment regimen of hourly lubrication with ointment, the patient's corneal epithelium appeared to be irregular on the next day, though no staining defects were noted. Tobramycin 0.3% ointment was added four times daily for prophylaxis, which the patient used only once because of discomfort. The next day he had three small areas of inferi or paralimbal moderately dense corneal stromal infiltrates with overlying epithelial defects. Corneal scrapings and cultures were performed and the patient was given ciprofloxacin 0.3% ophthalmic solution hourly. One day later, the infiltrate worsened and 24-hour culture results disclosed methicillin-sensitive Staphylococcus epidermidis resistant to ciprofloxacin and sensi tive to cefazolin (Table). The patient's treat ment was switched to topical cefazolin 50 m g / ml, hourly, and the infiltrate resolved and the corneal epithelium healed within the next three weeks. Case 2 A 63-year-old woman with a central corneal ulcer was referred to the Krieger Eye Institute. The patient had undergone previous uncompli cated extracapsular cataract extraction for a mature cataract several years earlier. Her post operative visual acuity was counting fingers because of diabetic retinopathy. Examination disclosed a dense stromal infiltrate with an overlying epithelial defect. Cultures and scrap ings of the ulcer were performed. The patient was treated with ciprofloxacin 0.3% ointment every two hours according to the protocol in an ongoing investigation with Alcon Laboratories on the safety and efficacy of ciprofloxacin oint-
© A M E R I C A N JOURNAL OF OPHTHALMOLOGY 114:336-338, SEPTEMBER, 1992
Ciprofloxacin-resistant Bacterial Keratitis
Vol. 114, No. 3
TABLE SENSITIVITIES TO ORGANISMS CULTURED FROM BACTERIAL KERATITIS* STAPHYLOCOCCUS
XANTHOMONAS
EPIDERMIS
MALTOPHILA
MIC-90 (MG/ML)
MICeo (MS/ML)
ANTIBIOTIC
CASE1
CASE 2
CASE 3
Amikacin Cefazolin Ceftazidime Ceftriaxone Chloramphenicol Ciprofloxacin Clindamyoin Gentamlcln Oxacillin Penicillin Ticarcillin Tobramycin Vancomycin
—
—
>32R
£1 S
4R
— —
— —
> 16 R >2R < 0.12 S >8R <0.5S >8R
8S >2R 0.25 S >8R >6R >8R
—
— —
4S 2S
2S
— 8S >32R
— >2R
— > 8R
— — 8S > 8 R
—
*S denotes sensitive; R denotes resistant; a dash indicates not tested.
ment in the treatment of bacterial keratitis. In the protocol of that study, patients are treated with ciprofloxacin ointment every two hours for the first 48 hours, and then every four hours at the discretion of the investigator. The corneal infiltrate improved on the first and second days after initiation of therapy and ciprofloxacin crystals were present on the stromal surface. The 48-hour culture results disclosed coagulase-negative S. epidermidis that was resistant to both cefazolin and ciprofloxacin, and that was sensitive to vancomycin (Table). Because of the initial favorable response to ciprofloxacin, the treatment with ciprofloxacin ointment was continued for 12 days. When the corneal infil trate failed to improve further, the patient's treatment was switched to topical vancomycin solution (50 mg/ml) every hour with a subse quent taper regimen. The patient's infiltrate cleared and the corneal epithelium healed with in the next 12 days. Case 3 A 53-year-old woman with a visual acuity of no light perception in the left eye because of uveitic glaucoma had a one-week history of pain and discharge from her blind left eye. Examina tion of the right eye disclosed a visual acuity of
337
20/25, a small hypopyon, and a mild vitreitis with perivenous sheathing of the retinal ves sels. Examination of the left eye disclosed mod erate conjunctival injection, moderate dis charge, a 4 x 5-mm dense central stromal infiltrate with an overlying epithelial defect, and a 2-mm hypopyon. Her medications at that time were timolol 0.5% instilled in the left eye twice daily and prednisolone acetate 1% ap plied to the left eye twice daily. Corneal scrap ings and cultures were performed, and the pa tient was treated hourly with ciprofloxacin 0.3% ophthalmic solution, three times a day with atropine sulfate 1% to both eyes, and twice a day with 40 mg of prednisone. Bacterial corneal ulcer in the left eye and Behçet's dis ease were diagnosed. The patient's corneal in filtrate did not improve over the next two days. The 48-hour culture results disclosed Xanthomonas maltophila resistant to ciprofloxacin and sensitive to ticarcillin (Table). When therapy was changed to hourly ticarcillin drops (4.1 mg/ml), the patient showed rapid initial im provement followed by gradual improvement over three weeks, but subsequently the epithe lium failed to heal and progressed to perfora tion.
Discussion The fluorinated quinolone antibiotics were first introduced for the treatment of systemic infections in the late 1980s. 1 Their use rapidly increased for the treatment of many systemic infections varying in severity from severe lifethreatening infections to fairly minor infec tions, such as uncomplicated urinary tract in fections. Initial experience with ciprofloxacin was positive and, although it remains a useful antibiotic for many severe infections, several resistant organisms have been detected. 24 The quinolones have more recently been in troduced to ophthalmology and appear to be effective in the treatment of corneal ulcers. Experimental animal studies 5,6 and more recent clinical trials 7 have shown that ciprofloxacin is an effective agent for infectious keratitis caused by a variety of organisms including methicillinresistant Staphylococcus species. It also appears to be effective in the treatment of experimental endophthalmitis (unpublished data from our laboratory, 1991). Ciprofloxacin offers the advantages of com-
338
September, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
mereiai availability, use as a single b r o a d - s p e c t r u m a g e n t , a n d g r e a t e r p o t e n c y in c o m p a r i s o n to other commercially available a n t i b i o t i c s . Leibowitz 7 found a n overall clinical success in 9 1 . 9 % of 148 corneal ulcers t r e a t e d w i t h c i p r o floxacin. Insler a n d associates 8 r e v i e w e d t w o cases of m e t h i c i l l i n - r e s i s t a n t S. aureus keratitis that were m a n a g e d successfully w i t h ciproflox acin. Ciprofloxacin h a s r a p i d l y b e c o m e t h e d r u g of choice in microbial keratitis for m a n y clinicians a n d is the only Food a n d D r u g A d m i n i s t r a t i o n - a p p r o v e d t r e a t m e n t for bacterial keratitis. Unlike a commercially p r e p a r e d eyed r o p , the p o t e n t i a l c o m p l i c a t i o n s of fortified p h a r m a c y - p r e p a r e d s o l u t i o n s are well k n o w n , s u c h as epithelial toxicity, p H v a r i a t i o n of t h e s o l u t i o n s , a n d c o n t a m i n a t i o n w i t h v i r u l e n t or ganisms. 8 1 1 The variable shelf life of h o s p i t a l p h a r m a c y - p r e p a r e d s o l u t i o n s also m a y limit the effectiveness of therapy. 1 2 1 3 At our i n s t i t u t i o n we have b e e n u s i n g cipro floxacin to treat p a t i e n t s w i t h bacterial keratitis since August 1989, a n d it h a s b e e n o u r d r u g of choice since it b e c a m e c o m m e r c i a l l y available. Overall, our r e s u l t s w i t h ciprofloxacin have b e e n excellent'; h o w e v e r , t h e t h r e e cases of this s t u d y d e m o n s t r a t e t h a t ciprofloxacin-resistant o r g a n i s m s exist. A l t h o u g h satisfactory r e s u l t s may occasionally be achieved w i t h a n t i b i o t i c s to w h i c h the c u l t u r e d o r g a n i s m s s h o w in v i t r o resistance, 1 0 the p o o r clinical r e s p o n s e in o u r cases was in a c c o r d a n c e w i t h the in vitro resist a n c e of the c u l t u r e d o r g a n i s m . A l s o , after t r e a t ment with antimicrobial agents that displayed in vitro activity to the c u l t u r e d o r g a n i s m , clini cal i m p r o v e m e n t w a s r a p i d . We a t t r i b u t e t h e u l t i m a t e failure of t r e a t m e n t in C a s e 2 to t h e h i g h - d o s e oral corticosteroid t r e a t m e n t t h a t was r e q u i r e d to treat the c o n t r a l a t e r a l eye (right eye) a d e q u a t e l y , w h i c h r e t a i n e d useful v i s i o n . A l t h o u g h ciprofloxacin a p p e a r s to b e a n ex cellent b r o a d - s p e c t r u m a n t i b i o t i c t h a t can be u s e d as the initial t h e r a p y in bacterial k e r a t i t i s , initial c u l t u r e s are vital in t h e t r e a t m e n t of bacterial corneal ulcers a n d a n t i m i c r o b i a l a g e n t s may n e e d to b e modified in specific cases d e p e n d i n g o n the clinical r e s p o n s e a n d t h e antibiotic sensitivities of the b a c t e r i a c u l t u r e d .
References 1. Neu, H. C : Microbiologie aspects of fluoroquinolones. Am. J. Ophthalmol. 112(suppl.):15S, 1991. 2. Raviglione, M. C , Boyle, J. F., Mariuz, P., Pablos-Mendez, A., Cortes, H., and Merlo, A.: Ciproflox acin-resistant methicillin-resistant Staphylococcus aureus in an acute-care hospital. Antimicrob. Agents Chemother. 34:2050, 1990. 3. Daum, T. E., Schaberg, D. R., Terpenning, M. S., Sottile, W. S., and Kaufman, C. A.: Increasing resistance of Staphylococcus aureus to ciprofloxacin. Antimicrob. Agents Chemother. 34:1862, 1990. 4. Fisher, L. M., Lawrence, J. M., Josty, I. C , Hopewell, R., Margerrison, E. E., and Cullen, M. E.: Ciprofloxacin and the fluoroquinolones. New con cepts on the mechanism of action and resistance. Am. J. Med. 87:2S, 1989. 5. O'Brien, I. P., Sawush, M. R., Dick, J. D., and Gottsch, J. D.: Topical ciprofloxacin treatment of Pseudomonas keratitis in rabbits. Arch. Ophthalmol. 106:1444, 1988. 6. Reiddy, J. J., Hobden, J. A., Hill, J. M., Forman, K., and O'Callaghan, R. J.: The efficacy of topical ciprofloxacin and norfloxacin in the treatment of experimental Pseudomonas keratitis. Cornea 10:25, 1991. 7. Leibowitz, H. M.: Clinical evaluation of cipro floxacin 0.3% ophthalmic solution for treatment of bacterialkeratitis.Am.J.Ophthalmol.ll2(suppl.):34S, 1991. 8. Insler, M. S., Fish, L. A., Silbernagel, J., Hob den, J. A., O'Callaghan, R. J., and Hill, J. M.: Suc cessful treatment of methicillin resistant Staphylococcus aureus keratitis with topical ciprofloxacin. Ophthalmology 98:1690, 1991. 9. Petroutsos, G., Guimaraes, Y., and Pouliquen, Y.: The effect of concentrated antibiotics on the rabbit's corneal epithelium. Int. Ophthalmol. 7:65, 1984. 10. Jones, D. B.: Decision-making in the manage ment of microbial keratitis. Ophthalmology 88:815, 1981. 11. Olsen, R. J.: How exposed are we? Arch. Oph thalmol. 107:1131, 1989. 12. Bowe, B. E., Snyder, J. W., and Eiferman, R. A.: An in vitro study of the potency and stability of fortified ophthalmic antibiotic preparations. Am. J. Ophthalmol. 111:686, 1991. 13. Osborne, E., Baum, J. L., Ernst, C , and Koch, P.: The stability of ten antibiotics in artificial tear solutions. Am. J. Ophthalmol. 82:775, 1976.