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Case report

Ciprofloxacin microprecipitates and macroprecipitates in the human corneal epithelium

Eiferman, Richard A. MD∗,a,1; Snyder, James P. PhDb,1; Nordquist, Robert E. PhDc,1

Author Information
Journal of Cataract & Refractive Surgery: October 2001 - Volume 27 - Issue 10 - p 1701-1702
doi: 10.1016/S0886-3350(01)00893-8
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Abstract

Ciprofloxacin ophthalmic drops occasionally form deposits in the base of corneal ulcers.1 We report 4 corneal transplantation cases treated with ciprofloxacin that were used to study the nature of the precipitates that developed, whether the drug was bioactive and bioavailable, and whether ciprofloxacin microprecipitates formed when the drug was administered before surgery.

Case reports

Four patients having corneal transplantation received 1 drop of commercially available ciprofloxacin 0.3% ophthalmic drops (Ciloxan®) at 5-minute intervals 4 times before surgery. The patients comprised 1 case each of a well-healed traumatic scar, keratoconus, bullous keratopathy, and chronic herpetic keratitis. As soon as the buttons were removed, they were bisected and one half was placed in glutaraldehyde 3% and submitted for scanning electron microscopy (SEM).

A large macroprecipitate developed in a 75-year-old woman with herpes zoster ophthalmicus; she developed a sterile corneal ulceration that progressed to an impending perforation. She had been treated prophylactically with Ciloxan drops 4 times daily for 1 week. At the time of corneal transplantation, the precipitate was removed with a forceps and a sample was submitted for high-pressure liquid chromatography (HPLC).

The remaining specimens were placed on a blood-agar plate seeded with a susceptible stain of Staphylococcus aureus (ATCC 29213). A standardized laboratory disk of ciprofloxacin containing 5 μg/mL served as a control. One-half of the keratoconus specimen, which received 4 drops of Ciloxan preoperatively, was also placed on a blood-agar plate as a control.

The keratoconus and traumatic scar specimens had normal corneal epithelia and were unremarkable by SEM. The other corneal buttons demonstrated characteristic crystalline ciprofloxacin particles associated with areas of damaged corneal epithelium (Figure 1). There was no adherence to the normal cornea. The excised macroprecipitate demonstrated a zone of inhibition that measured 32.0 mm; the control disk measured 27.0 mm after 24 hours (Figure 2). The macroprecipitate was removed and placed on a new agar plate 48 hours later with identical results. There was no growth from the control cornea.

Figure 1.
Figure 1.:
(Eiferman) Ciprofloxacin particles associated with areas of epithelial defects seen on SEM (original magnification ×6000).
Figure 2.
Figure 2.:
(Eiferman) A: Blood-agar plate seeded with a susceptible strain of S aureus. B: Standardized laboratory control disk with an inhibition zone of 27.0 mm. C: Ciprofloxacin precipitate with an inhibition zone of 32.0 mm.

Discussion

Wilhelmus et al.2 analyzed precipitates isolated from patients receiving ciprofloxacin ophthalmic ointment and discovered they comprised pure drug using HPLC. Leibowitz3 also analytically identified the crystalline deposits as ciprofloxacin. The precipitates did not have an adverse effect on the initial clinical trials and did not affect the healing rate or eventual outcome.

These findings suggest that ciprofloxacin forms microscopic precipitates that attach to areas of damaged human corneal epithelium. No gross precipitates were visible under the operating microscope or postoperatively by slitlamp biomicroscopy. The in vitro macroprecipitate experiment implies the drug can redissolve and retain bioactivity. If this occurs in vivo, the drug residue may explain the excellent cure rates of ciprofloxacin in ocular infection since it may serve as a depot that resolubilizes and releases the drug.

References

1. Hyndiuk RA, Eiferman RA, Caldwell DR, Caldwell DR, et al. Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramycin-cefazolin in treating bacterial corneal ulcers. Ophthalmology 1996; 103:1854-1862; discussion by ED Donnenfeld, 1862−1863
2. Wilhelmus KR, Hyndiuk RA, Caldwell DR, et al. 0.3% ciprofloxacin ointment in the treatment of bacterial keratitis. Arch Ophthalmol 1993; 111:1210-1218
3. Leibowitz HM. Clinical evaluation of ciprofloxacin 0.3% ophthalmic solution for the treatment of bacterial keratitis. Am J Ophthalmol 1991; 112(suppl):34S-47S
© 2001 by Lippincott Williams & Wilkins, Inc.