J Med Sci 2002;22(6):289-292 http://jms.ndmctsgh.edu.tw/2206289.

pdf Copyright 2002 JMS

Jy-Been Liang, et al.

New Protocol to Treat Corneal Ulcer: 2 Years Retrospective Experience

Jy-Been Liang*, Seng-Te Hong, Jiang-Tong Chen, Shang-Yi Cheng, and Cheng-Jong Chang Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China Background: To show the clinical efficacy of combined 0.3% Norfloxacin with 5% fortified cefazoline as the first line treatment for severe infective corneal ulcer. Methods: We retrospectively reviewed the admission charts of 29 patients with severe infective corneal ulcer from August 1, 1999 through July 31, 2001 who were initially given 0.3% norfloxacin with 5% fortified cefazoline as the first line treatment. The diagnosis of bacterial corneal ulcer was based on supportive clinical findings confirmed by microbiology (stain and culture); severity is defined as an epithelium defect greater than 2 mm and infiltration greater than 3 mm. Patients were treated with intensive topical antibiotics (combined 0.3% Norfloxacin, Baccidal, Santen Pharmaceutical Co., Japan and 5% fortified cefazoline) at a frequency of every half hour on the first day, every hour days 2 through 4, and every 2 hours on day 5 through the end of treatment. Results: Approximately 68.9% of patients were treated with topical antibiotics prior to admission. About 69% of the ulcer patients had a history of contact lens use at the time they developed corneal ulcers. The mean size of epithelial defect and infiltrate was 5.3 mm and 6.1 mm, respectively. Approximately 72.4% of ulcers were centrally located; the mean duration from attack to admission was 6.5 days. After admission, 100% of the corneal ulcer was scraped for smears and cultures, but 34.4% of culture results was positive. The mean duration of clinical response for intensive therapy was 3.2 days. Complete corneal reepithelization occurred in 93.1% of patients. Discussion: Combined 0.3% Norfloxacin with 5% fortified cefazoline as the first line treatment of severe bacterial corneal ulcer led to shorter duration of intensive therapy and high success rate and thus is suitable as the first line to treat severe corneal ulcer. The optical protocol for treatment of bacterial cornea ulcer is according to the culture result.
Key words: cornea, fluoroquinolone,infection, Norfloxacin, resistance

INTRODUCTION
Bacterial infections of the cornea may be associated with corneal ulceration and are among the leading causes of vision loss and blindness worldwide. Risk factors for bacterial keratitis include ocular trauma as well as contact lens wear in younger individuals and underlying ocular disease in older individuals. The treatment for severe bacterial corneal ulcers includes frequent administration of fortified topical ocular antibacterial agents and monotherapy with fluoroquinolone eye drops; monotherapy with fluoroquinolone eye drop resulted in shorter hospital stays compared with combined fortified therapy (Tobramycincefazoline)1.
Received: May 23, 2002; Revised: July 4, 2002; Accepted: July 12, 2002. * Corresponding author: Jy-Been Liang, Department of Ophthalmology, Tri-Service General Hospital, 7F-2, No. 40, LN. 211, Chung-Cheng Rd., Chung-Ho City 235, Taipei Hsien, Taiwan, Republic of China. Tel: +886-2-22424240; Fax: +886-2-22425509; e-mail: jb07@ms3.hinet.net

The fluoroquinolones are a class of potent antimicrobial agents with a broad spectrum of activity. In general, the fluoroquinolones have a high level of activity against Gram-negative organisms such as Pseudomonas aeruginosa and Neisseria gonorrhea, and good to excellent activity against Gram-positive organisms, including pencillinaseproducing, nonpenicillinase-producing, and methicillinresistant staphylococci, and most Gram-negative araerobes2. Norfloxacin is one of the fluoroquinolone antibiotics that is now extensively available as a topical ophthalmic preparation. It is particularly active against Gram-negative organisms, and also has good activity against Grampositive organisms except for some streptococci3,4. The observation of a rapid rise in fluoroquinolone resistance following introduction of ciprofloxacin for systemic use is noted. The increase in resistance was most pronounced in Gram-positive cocci, particularly Staphylococci species such as coagulase-negative Staphylococci. Among streptococci, almost one in four were resistant to ciprofloxacin in the time period following introduction of ciprofloxacin5,6. David G. Hwang et al. presented their
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findings at the 18th Asia-Pacific Ophthalmic conference, Taipei, Taiwan, 2001. They reported that 4 weeks of exposure to topical fluoroquinolones promoted the development of bacteria that had acquired multiple and presumably different mutations responsible for fluoroquinolone resistance. Therefore, they suggested that the proper indications for use of fluoroquinolones include contact lensassociated and other cases of uncomplicated bacterial keratitis in which fluoroquinolone monotherapy may be appropriate, and severe or complicated keratitis in which combining a beta-lactam like cefazoline along with the fluoroquinolone may be useful. In the current study, we use a new protocol (combined 5% fortified cefazoline with 0.3% Norfloxacin) for the treatment of corneal ulcers, and retrospectively review our medical records from August 1, 1999 to July 31, 2001.

admission. About 69% of the ulcers patients had a history of contact lens use at the time they developed keratitis (Table 1). The mean sizes of the epithelial defect and infiltrate were 5.3 mm and 6.1 mm, respectively. About 72.4% of ulcers were centrally located; the mean duration from attack to admission was 6.5 days. After admission, 100% of the corneal ulcers were scraped for smears and cultures, but only 34.4% of culture results were positive. The mean duration of clinical response for intensive therapy was 3.2 days. Complete corneal reepithelization occurred in 27 (93. 1%) patients. The average time for corneal ulcer healing was 13.4 days. The rate of a positive culture is only 34.4% Pseudomonas aeruginosa was the most commonly recovered organisms (5/14, 31.2%) (Table 1). We show the clinical presentation of two cases of corneal ulcer that did not respond well to the treatment protocol and will offer different thinking processes. Case 1 A 22-year-old female with a history of contact lens use arrived at our hospital suffering for 1 month from a corneal ulcer. OPH condition was as follows: vision acuity X right eye, hand motion; left eye, 20/20. The right eye showed corneal ulcer in a central location with an infiltration lesion size of 3.5 4.5 mm (Fig. 1). Corneal scraping with corneal culture was performed. We used 0.3% Norfloxacin plus 5% fortified cefazoline as the first line treatment. The ulcer was not improved after 2 days of treatment. The culture of corneal specimen showed no growth. The culture of contact lens and condition solution grew Pseudomonas maltophilia. It is resistant to fluoroquinolone and sensitive to Amikin; when we substituted Amikin for treatment, the lesion improved and stabilized after 10 days (Fig. 2).

METHODS
We retrospectively reviewed the admission charts of 29 patients with severe infective corneal ulcer from August 1, 1999 through July 31, 2001 who were admitted to Corneal Department of Tri-Service General Hospital. The diagnosis of bacterial corneal ulcer was based on supportive clinical findings confirmed by microbiology (stain and culture); severity is defined as an epithelium defect greater than 2 mm and infiltration greater than 3 mm. Patients were treated with intensive topical antibiotics (combined 0.3% Norfloxacin, Baccidal, Santen Pharmaceutical Co., Japan and 5% fortified cefazoline) at a frequency of every half hour on the first day, every hour on days 2 through 4, and every 2 hours on day 5 through the end of treatment. During the hospital visit, the patients signs and symptoms of bacterial keratitis were recorded in the medical chart. Daily examinations included visual acuity testing and biomicroscopic evaluation to assess ulcer healing. A sterile spatula scraping was used directly to inoculate the culture material in blood agar, chocolate agar, potato dextrose agar, and thioglycollate broth. These specimens were processed and analyzed using standard protocols7.

Table 1 Bacteria isolates Organism Pseudomonas spp. Serratia marcescens Streptococcus pneumoniae Number 5 2 2 1 3 1 14 % of ulcers 35.7% 14.3% 14.3% 7.1% 21.5% 7.1% 100%

RESULTS
The charts of 29 patients with corneal ulcer were reviewed. All ulcers were treated with intensive topical antibiotics (combined Baccidal and 5% fortified cefazoline) at a frequency of every half on the first day, every hour on days 2 through 4, and every 2 hours on day 5 through the end of treatment. Approximately 68.9% of patients had been treated with topical antibiotics prior to
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Staphylococcus aureus Actinetobacter Klebsiella pneumoniae Totals:

Jy-Been Liang, et al.

Case 2 A 70-year-old male had a history of DM. After eye rubbing, he felt pain, photophobia, and blurred vision. Because the condition got worse, the patient was transferred to our hospital. After admission, visual acuity was 20/30 in the right eye and 20/25 in the left eye with correction; Ext. eye: normal appearance. The right eye cornea showed central epithelial defect with stromal infiltration of approximately 55 mm in size with hypopyon. After admission, scraping and culture was performed, and 5% fortified cefazoline and 3% Norfloxacin was administered as protocol. The patient felt comfortable but hypopyon persisted 3 days later. We substituted cefazoline with piperacillin (q1h) in response to the culture result (Staphylococcus aureus which is resistant to cefazoline but is sensitive to piperacillin); the condition began to stabilize.

DISCUSSION
Topical fluoroquinolone offers the advantage of broadspectrum monotherapy which is commercially available. Most studies using the rabbit bacterial keratitis model showed that the fluoroquinolones were at least as effective or more effective than conventional therapies such as tobramycin, cefazoline, and vancomycin8-10. However, several reports have demonstrated that the Gram-positive coverage of the fluoroquinolone antibiotics may be suboptimal11,12. The possibility of mutational resistance resulting from low-dose exposure to fluoroquinolones has been investigated. Hwang et al. administered a tapering dose of topical ciprofloxacin to patients for 1 month prior to cataract surgery. They found a statistically significant increase in

ciprofloxacin-resistant Staphylococci isolated from eyelid flora, suggesting that de novo resistance was induced by low-dose exposure to the antibiotic (presented at the Annual Meeting of the Ocular Microbiology and Immunology Group, Chicago, 1996 and the 18th Asia-Pacific Ophthalmology conference). Therefore, they suggested that the proper indications for use of fluoroquinolones include the following: contact lens-associated and other cases of uncomplicated bacterial keratitis in which fluoroquinolone monotherapy may be appropriate, and severe or complicated keratitis in which combining a beta-lactam like cefazoline along with the fluoroquinolone may be useful. In our study, approximately 69.9% of patients have been treated with topical antibiotics prior to presentation and only 34.4% positive culture was found. It may be due to the higher rate of administration of topical antibiotic treatment in our patients prior to presentation. Contact lens wear is a major etiology of corneal ulcer; approximately 69% of the patients have a history of contact lens wear in our study. The risk increases significantly in patients who wear contact lens overnight. The average duration of clinical response for intensive therapy is 3.2 days in our study with a high cure rate of 93.1% compared with 62.1% and 85% in studies by Dr. Pavesio and Prajna et al.1,13, with fluoroquinolone monotherapy. It may be due to the bacteria resistance to fluoroquinolone. The high cure rate can be compared to the monotherapy with fluoroquinolone in which even the positive culture rate is low. The mean duration of clinical response for intensive therapy was 3.2 days. Two cases in our study showed that the protocol was used for 3 days without improvement of corneal ulcer, warranting a change in medication to treat the infection. We have concluded that 3 days is a key point in determining whether or not the protocol is useful.

Fig. 1 Corneal ulcer in central location with infiltration, lesion size: 3.5 4.5 mm.

Fig. 2 The lesion improved and stabilized after 10 days.

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REFERENCES
1. Prajna NV, George C, Selvaraj S, Lu KL, McDonnell PJ. Bacteriologic and clinical efficacy of ofloxacin 0.3% versus ciprofloxacin 0.3% ophthalmic solutions in the treatment of patients with culture-positive bacterial keratitis. Cornea 2001;20:175-178. 2. Wolfsan JS, Hooper DC. The fluoroquinolones: clinical and laboratory consideration. Clin Microbiol News 1991;14:1-7. 3. Osato MS, Jensen HG, Trousdale MD, Bosso JA, Borrmann LR, Frank J, Akers P. The comparative in vitro activity of ofloxacin and selected ophthalmic antimicrobial agents against ocular bacterial isolates. Am J Ophthalmol 1989;108:380-386. 4. Cutarelli PE, Lass JH, Lazarus HM. Topical fluoroquinolone:antimicrobial activity and in vitro corneal epithelial toxicity. Curr Eye Res 1991;10:557563. 5. Daum TE, Schaberg DR, Terpenning MS. Increasing resistance of Staphylococcus aureus to ciprofloxacin. Antimicrob Agents Chemother 1990;34:1862. 6. Jones DB. Emerging antibiotic resistance: real and relative (editorial). Arch Ophthalmol 1996;114:91-92.

7. Chin NX, Neu HC. Post antibiotic suppressive effect of ciprofloxacin against gram-negative bacteria. Am J Med 1987:82(Suppl 4A):58-62. 8. Guzek JP, Chacko D, Kettering JD. Comparison of topical ciprofloxacin to conventional antibiotic therapy in the treatment of experimental Pseudomonas aeruginosa keratitis. Cornea 1994;13:500-504. 9. Callegan MC, Engel LS, Hill JM, OCallaghan RJ. Ciprofloxacin versus tobramycin for the treatment of staphylococcal keratitis. Invest Ophthalmol Vis Sci 1994;35:1033-1037. 10. Lauffenburger MD, Cohen KL. Topical ciprofloxacin versus topical fortified antibiotics in rabbit models of Staphylococcus and Pseudomonas keratitis. Cornea 1993;12:517-521. 11. Snyder ME, Katz HR. Ciprofloxacin-resistant bacterial keratitis. Am J Ophthalmol 1992;114:336-338. 12. Maffett M, ODay DM. Ciprofloxacin-resistant bacterial keratitis (editorial). Am J Ophthalmol 1993;115: 545-546. 13. Pavesio C. Ofloxacin monotherapy for the primary treatment of microbial keratitis. Ophthalmol 1997:104: 1902-1909.

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