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Jy-Been Liang, et al.J Med Sci 2002;22(6):289-292http://jms.ndmctsgh.edu.tw/2206289.pdfCopyright 2002 JMS

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

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. About69% 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: Com-

bined 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 bac-

terial 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 stayscompared with combined fortified therapy (Tobramycin-

cefazoline)1.

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 pencillinase-

producing, nonpenicillinase-producing, and methicillin-

resistant staphylococci, and most Gram-negative ara-

erobes2.

Norfloxacin is one of the fluoroquinolone antibiotics

that is now extensively available as a topical ophthalmic

preparation. It is particularly active against Gram-nega-tive organisms, and also has good activity against Gram-

positive organisms except for some streptococci3,4.

The observation of a rapid rise in fluoroquinolone

resistance following introduction of ciprofloxacin for sys-

temic use is noted. The increase in resistance was most

pronounced in Gram-positive cocci, particularly Staphylo-

cocci 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 ex-

posure to topical fluoroquinolones promoted the develop-

ment of bacteria that had acquired multiple and presum-

ably different mutations responsible for fluoroquinolone

resistance. Therefore, they suggested that the proper indi-

cations for use of fluoroquinolones include 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 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.

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 Cor-

neal Department of Tri-Service General Hospital. The di-

agnosis of bacterial corneal ulcer was based on support-

ive 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 (combined0.3% 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 symp-

toms 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 dex-

trose agar, and thioglycollate broth. These specimens were

processed and analyzed using standard protocols7.

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

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 in-

filtrate 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 recov-

ered organisms (5/14, 31.2%) (Table 1). We show the clini-

cal presentation of two cases of corneal ulcer that did not

respond well to the treatment protocol and will offer dif-ferent 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 cor-

neal 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 infiltra-

tion lesion size of 3.5 4.5 mm (Fig. 1). Corneal scrap-

ing 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 oftreatment. 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 sub-

stituted Amikin for treatment, the lesion improved and sta-

bilized after 10 days (Fig. 2).

Table 1 Bacteria isolates

Organism

Pseudomonas spp.

Serratia marcescens

Streptococcus pneumoniae

Staphylococcus aureus

Actinetobacter

Klebsiella pneumoniae

Totals:

Number

5

2

2

1

3

1

14

% of ulcers

35.7%

14.3%

14.3%

7.1%

21.5%

7.1%

100%

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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 trans-

ferred 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 infil-

tration of approximately 55 mm in size with hypopyon.

After admission, scraping and culture was performed, and

5% fortified cefazoline and 3% Norfloxacin was adminis-

tered as protocol. The patient felt comfortable but hy-

popyon 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 tostabilize.

DISCUSSION

Topical fluoroquinolone offers the advantage of broad-

spectrum monotherapy which is commercially available.

Most studies using the rabbit bacterial keratitis model

showed that the fluoroquinolones were at least as effec-

tive 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 besuboptimal11,12.

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 An-

nual Meeting of the Ocular Microbiology and Immunol-

ogy Group, Chicago, 1996 and the 18th Asia-Pacific Oph-

thalmology 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 compli-

cated 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 treat-ment 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 clini-

cal 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 bacte-

ria 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 du-ration 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 determin-

ing 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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