Microbial resistance: a concern for the future

Issue: September 2005

ByJennifer Byrne

The newer-generation fluoroquinolones Zymar (gatifloxacin, Allergan) and Vigamox (moxifloxacin, Alcon) are well regarded for their ability to combat ocular infections such as infectious keratitis.

As with previous-generation fluoroquinolones, however, resistance to the newer-generation agents seems inevitable. In fact, shifts have already occurred in the prominence of gram-positive and gram-negative organisms related to these infections.

Despite these trends, practitioners maintain that newer-generation fluoroquinolones are still the most effective approach to treating infectious keratitis.

“For the present time, the fourth-generation fluoroquinolones remain the best ophthalmic medications we have for prophylaxis,” said Eric D. Donnenfeld, MD, a cornea specialist in private practice at Ophthalmic Consultants of Long Island and co-chairman of Cornea and External Disease at Manhattan Eye, Ear and Throat Hospital. “However, they are not universally effective, and we need to continue to develop better antibiotics, particularly against gram-positive bacteria.”

Pendulum swing

At the beginning of the 1990s, most cases of infectious keratitis were related to gram-negative organisms, particularly Pseudomonas. Throughout the decade, however, a “pendulum swing” occurred, with gram-negative organisms becoming less of a concern and gram-positive organisms emerging as a problem. (Varaprasathan G et al. Trends in the etiology of infectious corneal ulcers at the F. I. Proctor Foundation. Cornea. 2004;23(4):360-364.)

Because the new fluoroquinolones are designed specifically to respond to this gram-positive concern, it has been suggested that gram-negative organisms may again become a threat.

Eric D. Donnenfeld, MD [photo]
Eric D. Donnenfeld

While Dr. Donnenfeld acknowledged the reality of microbial resistance, he maintained that the newer-generation fluoroquinolones are still the best resource available for fighting both gram-positive and gram-negative organisms. He discussed the recent progression and evolution of antibiotics.

“During the past two decades, there have been three major advances in ophthalmic antibiotics,” he told Primary Care Optometry News. “They are the aminoglycosides such as tobramycin and gentamicin, the second-generation fluoroquinolones such as ofloxacin and ciprofloxacin, and, finally, the most recent advance, which is the fourth-generation fluoroquinolones.”

Dr. Donnenfeld said that each of these three groups of medications has shown improved efficacy against gram-positive bacteria such as Staphylococcus and Streptococcus.

“However, all three of these groups have had much better efficacy against gram-negative bacteria, and each group has advanced by providing broader coverage,” he said. “Unfortunately, resistance to these medications continues to be primarily in the group of gram-positive bacteria, with Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus continuing to be the major concerns. More than 90% of infections following cataract surgery, LASIK and PRK are due to these organisms.”

According to Regis P. Kowalski, M(ASCP), manager and associate director of the Charles T. Campbell Eye Microbiology Lab, a trend back toward gram-negative resistance is not imminent. “This is possible, but I do not see any trends occurring,” he said in an interview with Primary Care Optometry News.

Resistance studies

A study presented by Dr. Kowalski at the 2002 Ocular Microbiology and Immunology Group (OMIG) meeting looked at the future benefits of the newer fluoroquinolones in combating bacterial keratitis.

According to the study abstract, gatifloxacin and moxifloxacin showed greater effectiveness in fighting gram-positive bacteria than did the previous-generation fluoroquinolones levofloxacin, ciprofloxacin and ofloxacin. The newer-generation drugs were also more effective against isolates that had been unresponsive to second- and third-generation agents.

Using e-tests, the clinicians established the MICs of 177 bacterial keratitis isolates. Bacterial susceptibilities were formulated using the NCCLS standards and were compared statistically. Potencies (isolates with the lowest MICs) were also determined.

The study concluded that while they demonstrated superior gram-positive coverage, newer-generation fluoroquinolones demonstrated no advantage over the previous generation drugs for gram-negative coverage.

Another study conducted at the Bascom Palmer Eye Institute by Darlene Miller and colleagues and presented at the OMIG 2003 meeting examined in vitro resistance rates for fluoroquinolones against methicillin-sensitive (MS) and methicillin-resistant (MR) S. aureus ocular isolates.

The study determined that both MS and MR isolates demonstrated fluoroquinolone resistance. The resistance rates for methicillin-sensitive S. aureus were 7% for moxifloxacin, 9% for gatifloxacin, 13% for levofloxacin, 16% for ofloxacin and 16% for ciprofloxacin. In vitro resistance rates for methicillin-resistant isolates were 77% for moxifloxacin, 81% for gatifloxacin, 81% for levofloxacin, 88% for ciprofloxacin and 88% for ofloxacin.

Future implications

Dr. Donnenfeld said developing stronger antibiotics must remain a priority. Dr. Kowalski said in the event of fluoroquinolone resistance, gram-negative infections could be treated with ciprofloxacin 0.5% or tobramycin 14 mg/mL.

The possibility of emerging microbial resistance may have implications in terms of treating post-LASIK infectious keratitis. However, Dr. Donnenfeld said he still turns to the newer-generation fluoroquinolones.

“For the present time, I recommend treating post-LASIK infectious keratitis with fluoroquinolones such as Zymar or Vigamox, which provide excellent gram-negative coverage, but not universally great coverage against gram-positives,” he said. “I also recommend that a second antibiotic with specific gram-positive coverage such as cefazolin 50 mg/mL or vancomycin 35 mg/mL be given on an alternating basis with the fourth-generation fluoroquinolones.”

Dr. Kowalski said he is not especially worried about the implications of microbial resistance in terms of treating post-LASIK infectious keratitis. “I wouldn’t worry about it,” he said. “The concentrations of the fourth-generation fluoroquinolones are so high with topical therapy that gram-negative infections will seldom occur.”

For Your Information:

Eric D. Donnenfeld, MD, is a cornea specialist in private practice at Ophthalmic Consultants of Long Island and co-chairman of Cornea and External Disease at Manhattan Eye, Ear and Throat Hospital. He can be reached at Ryan Medical Arts Bldg., 2000 North Village Ave., Rockville Centre, NY 11570; (516) 766-2519; fax: (516) 766-3714. Dr. Donnenfeld is a paid consultant for Allergan and Alcon.

Regis P. Kowalski, M(ASCP), is manager and associate director of the Charles T. Campbell Eye Microbiology Lab. He can be reached at 203 Lothrop St., Pittsburgh, PA 15213; (412) 647-7211; fax: (412) 647-5331. Mr. Kowalski does contract research for Alcon and Allergan.