Fluoroquinolones: is there a need to choose?

Issue: July 2000

Practitioners can consult an abundance of studies when deciding which topical ophthalmic fluoroquinolone to use, but many wonder whether the choice is a clinically significant one.

The June 15, 2000, issue of our sister publication, Ocular Surgery News, featured a series of articles addressing the differences between ciprofloxacin and ofloxacin by addressing surface prophylaxis, corneal penetration and clinical results.

The differences found between ciprofloxacin (Ciloxan, Alcon) and ofloxacin (Ocuflox, Allergan) in the lab might make little or no difference in everyday use, some practitioners said. The drugs have varying properties in vitro, to be sure, and these differences are spelled out at scientific meetings and in literature in great detail. But in vivo, surgeons have taken to picking up the bottles out of habit or in response to a pharmaceutical representative’s sales call. The fact that users of both drugs have excellent clinical results is a testament to the power of the fluoroquinolones as a drug class.

Both work well

According to Kenneth R. Kenyon, MD, of the debate between ciprofloxacin and ofloxacin, “My sense is that it almost invariably does not make a difference. If one adapts a conservative clinical management style and uses prophylactic antibiotics at the appropriate dosage for at least 1 or 2 days preoperatively and three to four times per day preoperative dosing … then the two drugs in question have great clinical equivalency.”

According to Michael A. Lemp, MD, “I know that there are theoretical differences why people prefer one over the other and it is a big campaign. There’s this tremendous competition between the two [companies] for the antibiotic market.”

Most clinicians are creatures of habit and will stick with one quinolone for all uses after finding that one works well.

Still, Dr. Lemp said, “There’s no question about it, they both work well. They have broad-spectrum coverage. You could make a case for either of them. But I don’t think that you can make a case that one is obviously superior clinically to the other.”

Effect on corneal cells

Because antibiotics may have cytotoxic side effects on corneal cells, which could negatively affect wound healing, Terrence P. O’Brien, MD, studied ciprofloxacin, ofloxacin and gentamicin on culture dishes and rabbit models. His work was supported by an unrestricted educational grant from Alcon (Ft. Worth, Texas).

In the rabbit study, Dr. O’Brien concluded that ofloxacin and gentamicin showed the greatest evidence for keratocyte depletion and edema. Ciprofloxacin was the least cytotoxic, with a significantly lower amount of positive stromal cells undergoing apoptosis at day 1. It also offered the best results for epithelial healing and the most normal stromal appearance at day 5.

Dr. O’Brien noted: “ … even the control group had an increase in keratocyte depletion at day 5 just with the wounding of the cornea.”

According to microbiologist Regis P. Kowalski, Dr. O’Brien’s study is well constructed for studying in vitro effects. But clinical use does not hold up the distinction. While ofloxacin may be slightly more toxic than ciprofloxacin in laboratory studies, he said, “I don’t know of any reports of oflox being more toxic than cipro in clinical situations.”

Post-PRK healing

Richard W. Yee, MD, presented a study at the Association for Research and Vision in Ophthalmology meeting in 1998 that examined epithelial healing after photorefractive keratectomy (PRK). One group of patients received ofloxacin, a second group received ciprofloxacin and a third group received ofloxacin with artificial tears.

Study results showed that the recovery time from PRK to healing was 85 hours in the ofloxacin group, 129 hours in the ciprofloxacin group and 68.5 hours in the ofloxacin/artificial tears group.

According to Calvin W. Roberts, MD, ofloxacin and ciprofloxacin are comparable in their effects on the corneal epithelium and endothelium. “Even though this study shows that the ofloxacin was less toxic, the bottom line is that I don’t think there’s a difference in terms of epithelial toxicity,” he said. “The issues between the drugs are really those in terms of formulation and penetration. Those are the only two areas where I think there’s a difference at all.”

Reducing ocular surface flora

Harold R. Katz, MD, uses ciprofloxacin because he said it is more potent against the organisms that cause endophthalmitis. He performed a study to determine which quinolone reduces ocular surface flora more effectively, as well as to determine the time course of the effect of these antibiotics during the perioperative period.

He studied three groups of 20 human eyes. The first group received three drops of ciprofloxacin 0.3% 5 minutes apart. The second group received three drops of ofloxacin 0.3% 5 minutes apart. The third group was untreated.

Dr. Katz said that the ciprofloxacin group experienced a “rapid and dramatic” reduction in bacterial colony counts. The counts dropped by 97% at 15 minutes and 98% for each other time point. Eyes treated with ofloxacin showed a 49% reduction at 15 minutes, a 43% reduction at 30 minutes, a 34% reduction at 1 hour and a 73% reduction at 2 hours. He concluded that ciprofloxacin was statistically significantly better than ofloxacin at each time point in the study.

According to Dr. Kenyon, specific issues such as time-kill curves are important considerations in the in vivo capabilities of a single application or dosage of a drug to eradicate susceptible organisms over a short interval of time. These tests have been used, for example, to demonstrate the superiority of ciprofloxacin preparations. However, good in vivo studies by other investigators also verify ofloxacin’s efficacy.

“But what is the real way we practice clinical medicine?” Dr. Kenyon asked. “Most ophthalmic surgeons tend to commence prophylaxis for at least a few days preoperatively. Consequently, the kill curve advantage is probably somewhat lessened in terms of clinical reality.”

Aqueous penetration

Frank A. Bucci Jr., MD, sought to determine if ciprofloxacin or ofloxacin offers more penetration into the aqueous and could treat possible contamination of the anterior segment. Group 1 received one of the fluoroquinolones four times a day for 2 days before phacoemulsification. Group 2 received five drops every 10 minutes immediately preoperatively. Group 3 received one of the fluoroquinolones by means of a pledget. Group 4 received the drugs by a pledget soaked with a cocktail of fluoroquinolones, nonsteroidal anti-inflammatory drugs and dilation drops. Samples of aqueous before starting phaco were analyzed.

Group 2 showed the highest levels of fluoroquinolones. Ofloxacin patients had 707 ng/mL and ciprofloxacin patients had 208 ng/mL in their aqueous samples. About 3.5 times the levels of ofloxacin were found in the aqueous humor in all four techniques. The minimum inhibitory concentration (MIC) levels for the most common pathogens that cause endophthalmitis were achieved for all four delivery methods with ofloxacin.

According to other studies that were conducted by Dr. Roberts, ofloxacin penetrates into the aqueous five times as well and into the deep cornea three times as well as ciprofloxacin. “With preoperative antibiotics prior to cataract surgery, I try to achieve the levels of drug that will be inhibitory for bacterial growth should bacteria be inoculated into the anterior chamber during the cataract operation,” he said.

Dr. Roberts gives all his patients ofloxacin four times per day for 3 days prior to surgery.

For refractive surgery, Dr. Roberts said he uses ofloxacin to attack the gram-negative Pseudomonas strains. Both ofloxacin and ciprofloxacin concentrations contain thousands of times more drug than needed to kill bacteria on the corneal surface.

Henry D. Perry, MD, said he regularly uses ofloxacin because of the penetration issues. However, he added that he will switch to ciprofloxacin in contact lens wearers, who frequently suffer from Pseudomonas infections.

Eradicate bacteria on ocular surface

According to Dr. Katz, what is important is not the preoperative or postoperative aqueous concentrations, but eradicating the bacteria on the ocular surface before they enter the eye. By the time the surgeon irrigates hundreds of cc’s of fluid intraoperatively, the pre-existing drug concentration has probably fallen to zero.

“The only way that it would be of any use to have a therapeutic concentration of antibiotic in the anterior chamber is if it were present after surgery,” Dr. Katz said. However, antibiotics in the anterior chamber only have a half-life of 2 hours. Even direct injections into the anterior chamber do not last long enough to be therapeutic. Furthermore, he said, MIC levels are the minimum needed to inhibit the growth of an organism. The minimum bactericidal concentration (MBC) is more important and requires a higher concentration of antibiotic.

“That’s why the issue of penetration of topical antibiotic into the aqueous is irrelevant,” Dr. Katz said. “You’re achieving subtherapeutic levels and you’re measuring them prior to all the irrigation that occurs during cataract surgery.

“Every piece of evidence we know indicates that the only way to prevent postoperative infection is to kill organisms on the ocular surface before they enter the eye and cause an infection,” he continued. “In fact, we have shown that topical ciprofloxacin is much more effective than topical ofloxacin in reducing ocular surface flora on the eyes of human subjects.”

According to Mr. Kowalski, ofloxacin might penetrate faster, but the drugs reach the same concentrations eventually. “ If you get better penetration in a short time, oflox may have an advantage because it does have a higher concentration into the aqueous,” he said. “But, generally, you don’t need as much ciprofloxacin to kill as you do with ofloxacin.”

For Your Information:

Kenneth R. Kenyon, MD, can be reached at Corneal Consultants, 100 Charles River Plaza, Ste. 301, Boston, MA 02114; (617) 523-2010; fax: (617) 523-4242; e-mail: kkenyon@compuserve.com. Dr. Kenyon has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Michael A. Lemp, MD, can be reached at University Ophthalmology Consultants, 4910 Massachusetts Ave. NW, Ste. 210, Washington, DC 20016; (202) 686-6800; fax: (202) 686-6668. Dr. Lemp has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Terrence P. O’Brien, MD, can be reached at the Wilmer Eye Institute, 600 N. Wolfe St., Wilmer Woods 225, Baltimore, MD 21287; (410) 955-1671; fax: (410) 614-0682.

Regis P. Kowalski can be reached at the University of Pittsburgh Eye and Ear Institute, Bldg. 203 Lothrop, Pittsburgh, PA 15213-2582; (412) 647-7211; fax: (412) 647-5311. Mr. Kowalski has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Calvin W. Roberts, MD, can be reached at 520 E. 70th St., Suite Starr817, New York, NY 10021; (212) 734-7788; fax: (212) 734-4476. Dr. Roberts has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Harold R. Katz, MD, can be reached at Sinai Hospital of Baltimore, 2411 W. Belvedere Ave., Baltimore, MD 21215; (410) 601-5991; fax: (410) 601-6284. Dr. Katz has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Frank A. Bucci Jr., MD, can be reached at 158 Wilkes-Barre Township Blvd., Wilkes-Barre, PA 18702; (570) 825-5949; fax: (570) 825-2645. Dr. Bucci has no direct financial interest in the products mentioned in this article. He has received a research grant from Allergan.

Henry D. Perry, MD, can be reached at 2000 N. Village Ave., Suite 302, Rockville Center, NY 11570; (516) 766-2519; fax: (516) 766-3714. Dr. Perry has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Alcon can be reached at 6201 South Freeway, Fort Worth, TX 76134; (800) 862-5266; fax: (817) 241-0677.

Allergan can be reached at 2525 Dupont Drive, Irvine, CA 92612; (800) 366-6554; fax: (800) 752-7006.