ANTIBIOTIC EFFICACY

A Higher Concentration Antibiotic

A new-generation fluoroquinolone achieves high drug concentrations in tears, cornea and aqueous.

By Randall K. Thomas, OD

Dr. Thomas is in clinical practice in Concord, N.C. He is a consultant and speaker for Vistakon pharmaceuticals. Contact him at thomasepec@carolina.rr.com.

In recent years, eyecare practitioners have had the benefit of several broad-spectrum topical fluoroquinolones with good efficacy against the most important ocular pathogens. New data released from large national bacterial infection databases confirms that gatifloxacin, levofloxacin and moxifloxacin continue to have similar efficacy and resistance patterns.

According to both their mechanisms of action and laboratory sensitivity testing, all three of these drugs should be considered in the same generation or antibiotic classification.

However, a higher 1.5% concentration of levofloxacin (Iquix, Vistakon Pharmaceuticals) may be raising the bar for those who are concerned about getting enough of their chosen antibiotic into ocular tissues for the longest period of time.

Ocular TRUST

A large national surveillance study known as Tracking Resistance in the U.S. Today, or TRUST, was launched in 1996 to track the development of antibiotic resistance. Since its inception, this project has collected a large database of 75,000 bacterial isolates, all of which have been centrally tested against a slate of different antibiotics.

A few years ago, Ocular TRUST was launched to gather ocular isolates and supplement the main TRUST study with information that would be relevant to eyecare practitioners.

"Ocular TRUST is unique in that it provides us with a very large sample size, so the data are much more reliable than what we've had in the past," said Christopher Ta, MD, associate professor of Cornea and External Diseases at the Stanford University School of Medicine. "It is going to be very important in our ability to detect trends in resistant organisms over time."

Already, the Ocular TRUST data have demonstrated that 100 percent of the 342 Streptococcus pneumoniae and Haemophilus influenzae ocular isolates collected in 2006 were susceptible to gatifloxacin, levofloxacin and moxifloxacin. The three broad-spectrum fluoroquinolones also had virtually identical susceptibility patterns for Staphylococcus aureus (Figure 1) and coagulase-negative Staphylococcus epidermidis.

Figure 1. The three broad-spectrum fluoroquinolones had virtually identical susceptibility patterns for Staphylococcus aureus and coagulase-negative Staphylococcus epidermidis.

The good news is that all three newer-generation fluoroquinolones, as a class, are effective against most of the ocular organisms we deal with as eyecare providers. We also are able to deliver ocular antibiotics directly to the cornea's surface, where the bacteria are. The high kill rates have made bacterial resistance in the eyecare setting fairly rare.

Gatifloxacin, levofloxacin and moxifloxacin interfere with the bacteria-replicating properties of DNA-gyrase and topoisomerase IV. Because two separate mutations are necessary for the bacteria to become resistant to the antibiotics, the two-pronged approach has helped to prevent resistance.

Nevertheless, Ocular TRUST did show that incidence of methicillin-resistant S. aureus (MRSA) is rising. In laboratory testing, most antibiotics, including the newer-generation fluoroquinolones, have limited efficacy against MRSA and methicillin-resistant S. epidermidis (MRSE).

Maximizing Drug Exposure

According to Penny A. Asbell, MD, professor of ophthalmology and director of Cornea and Refractive Services at Mt. Sinai Medical Center in New York City, the most important consideration when selecting an antibiotic is that it has an appropriate spectrum of activity.

But given that all the newer-generation fluoroquinolones have the same spectrum of activity, how is a practitioner to choose among them?

"It's not enough to kill bacteria in a test tube," Dr. Asbell said. "We also want the drug to get into the target tissues and stay there long enough to be effective in vivo." This is where the high concentration of the newest fluoroquinolone on the market, levofloxacin 1.5%, may provide an edge.

In human studies, researchers studied what happens to the concentration of levofloxacin in the tear film over time after a single dose of Iquix. The C_max, or highest drug concentration, is achieved within the first 10-to-15 minutes. The concentration levels then are nearly 2,000 times more than what is required to kill 90 percent of S. aureus isolates (the MIC₉₀) and 242 times greater than the MIC₉₀ for the gram-negative bacteria Pseudomonas aeruginosa. Six hours after the single dose, tear concentrations of Iquix are still many times the MIC₉₀ for common ocular organisms (Figure 2). Even after 24 hours, tear concentrations remain significantly above MIC₉₀ levels.

Figure 2. Six hours after the single dose, tear concentrations of Iquix are still many times the MIC₉₀ for common ocular organisms.

"These data suggest that even if a patient is not as compliant as we would like, we are going to achieve a concentration level that is effective in treating or preventing infection," said Dr. Asbell.

Animal studies show that high concentrations in the tears are translating into high concentrations in the cornea and aqueous as well. When comparing Iquix to moxifloxacin (Vigamox, Alcon) and gatifloxacin (Zymar, Allergan), the total drug exposure in the cornea over a 12-hour period was more than two-fold higher for Iquix than for the other two drugs (Figure 3). Total drug exposure or area under the curve (AUC) of the aqueous humor was also greatest for Iquix (Figure 4).

Figure 3. The total drug exposure in the cornea over a 12-hour period was more than two-fold higher for Iquix than for the other two drugs.

Figure 4. Total drug exposure or area under the curve of the aqueous humor was also greatest for Iquix.

A study (Holland et al, 2007) that looked at drug concentrations in human corneal tissue and aqueous humor samples collected during previously planned penetrating keratoplasty found that concentrations of Iquix compared to Zymar were much greater than might be predicted from the higher concentration in the bottle.

"Moxifloxacin also achieves high peak concentrations, but it doesn't last as long in the tissue, so the total drug exposure is lower. Gatifloxacin doesn't penetrate quite as well or stay in the tissue as long, so its exposure is lower still. So of the three major broad-spectrum fluoroquinolones, Iquix seems to deliver more drug to the eye, whether we're looking at the tears, the cornea or the aqueous," Dr. Asbell said.

Treating Corneal Ulcers

In one recent case, Dr. Asbell saw a young female contact lens wearer with keratitis in one eye. Although the infection was not severe, the presentation was unusual. "There was one infiltrate that suggested a typical peripheral corneal ulcer, but also some odd-looking infiltrates throughout the cornea," Dr. Asbell said. Although she was still awaiting culture results, she started the patient on Iquix every hour. "That may have been overkill, but I wanted to impress upon the patient my level of concern, that this was not an insignificant little problem."

John D. Sheppard, MD, MMSc, professor of ophthalmology, microbiology and immunology at Eastern Virginia Medical School, noted that the new concentration has altered his dosing schedule.

"I find that we can start corneal ulcer patients on Iquix every hour without a loading dose because concentrations rapidly reach high levels," he said. "Previously, we would administer four drops of topical antibiotic over 15 minutes in the office to ‘load’ the cornea. Now we don't have to do that, and we can more quickly move from every hour to every two hours' administration, and then to four times a day as the infection improves. That is well ahead of the typical dosing schedule for other antibiotic agents."

He pointed out that infections caused by P. aeruginosa are among the indications for Iquix. "There is a gap in the susceptibility of Pseudomonas to moxifloxacin. Although Pseudomonas infections are rare, they are highly virulent and often devastating when they do occur. Thus, I believe moxifloxacin should not be a first-line or single therapeutic agent when treating contact lens-associated ulcers when Pseudomonas infection is highly likely," he said.

Although many clinicians use ophthalmic drugs off-label, they may be less likely to do so when there is an approved option. "Iquix is the only newer-generation fluoroquinolone that is FDA-approved for the treatment of corneal ulcers," said Dr. Ta, who sees at least one such case every day in his cornea clinic. "Because of its very high concentration in the cornea, levofloxacin 1.5% certainly is the ideal drug for the treatment of many corneal ulcers."

If the ulcer is large, centrally located or vision-threatening, however, he adds fortified vancomycin to the regimen to cover MRSA.

I have turned to an old antibiotic, trimethoprim, when MRSA is suspected. One of the things we learned from the Ocular TRUST data is that trimethoprim, which is available commercially as Bactrim (AR Scientific) or Septra (Monarch Pharmaceuticals), is very effective against MRSA.

Dr. Sheppard agrees. "I have personally treated infections that were initially cultured prior to treatment then later grew MRSA, yet responded well to Iquix," he said. "However, known MRSA infections or unidentified serious ocular surface infections are best treated with Iquix plus a topical aminoglycoside such as tobramycin and systemic sulfonamides such as oral Bactrim."

Tolerability and toxicity are other considerations when choosing an antibiotic for corneal or other infections. Our primary concerns are efficacy, penetration and duration of effect. But when giving a drop every one-to-two hours, you want it to be tolerable so that patients don't skip doses. With a pH of 6.5, Iquix is very comfortable. In vitro studies show it to be the least cytotoxic of the broad-spectrum fluoroquinolones to corneal keratocytes and endothelial cells (Figure 5). This may be due to the absence of benzalkonium chloride as a preservative.

Figure 5. In vitro studies have also shown Iquix to be the least cytotoxic of the broad-spectrum fluoroquinolones to corneal keratocytes and endothelial cells.

"We typically don't use ophthalmic fluoroquinolones for long enough to be concerned about cumulative toxicity from preservatives," said Dr. Sheppard. "However, eyes with infections are already exposed to a wide variety of toxic agents, so reducing surface toxicity as much as possible is an important consideration."

Preventing Infection

Although levofloxacin 1.5% seems to be emerging as a favorite for treating corneal ulcers, its exact place in the ophthalmic armamentarium is still in flux. How broadly will this new topical antibiotic be used for surgical prophylaxis, for example?

Dr. Sheppard said Iquix is his choice to treat corneal ulcers and for off-label uses, including severe bacterial conjunctivitis. "I also use it prophylactically for trabeculectomies, ocular surface surgical procedures such as scar removal, surface excimer laser ablation or phototherapeutic keratectomy, and in trauma cases with a high risk of infection, such as severe abrasion or foreign body."

Dr. Ta uses it a bit more broadly, as part of his prophylactic regimen for all intraocular surgery, including cataract surgery and corneal transplants.

Prophylactic antibiotic use in cataract surgery is controversial. Experts disagree on which drug to use, the timing and frequency of dosing and even whether surgical prophylaxis is necessary at all.

"We don't have the data to tell us whether one method is better than another," said Dr. Ta. "All we can say is that because most organisms that cause intraocular infections are on the ocular surface, anything we can do to minimize contamination of that surface, including antibiotics, is reasonable." For endophthalmitis prevention, he says, choose a broad-spectrum antibiotic to cover gram-positive and gram-negative organisms, and a bactericidal antibiotic to eliminate bacteria before and after surgery.

"The fluoroquinolones satisfy those needs," said Dr. Ta. "And among the fluoroquinolones, I think it just makes sense to use the one that can best penetrate the cornea and get into the eye where you want it. Certainly Iquix stands out right now as the drug that can best accomplish that."

Dr. Asbell uses Iquix prophylactically as she has used other ophthalmic antibiotics for years, keeping the dosing schedule the same as that of the postoperative steroid, for convenience and compliance. By her estimate, more than 90 percent of American ophthalmologists do use prophylactic antibiotics before and after cataract surgery to decrease the risk of infection, despite lack of definitive evidence that doing so reduces the rate of endophthalmitis.

The European Society of Cataract and Refractive Surgeons and Swedish researchers published analyses of endophthalmitis rates in Europe, based on large cataract surgery databases. Both determined that intraocular antibiotics at the end of surgery significantly reduced endophthalmitis risk. "American surgeons have been loath to adopt intraocular injections in routine cases," said Dr. Asbell. "But if we can achieve high drug concentration levels in the aqueous with levofloxacin 1.5%, we may be able to get the same benefit without the risk, nuisance and expense of specially formulated intraocular injections."

Putting it in Perspective

For now, Dr. Asbell says, levofloxacin 1.5% should be the choice for many applications. "No one should take that to mean that we don't need to have other antibiotics on hand or we don't need to culture in cases of sight-threatening infection. Some isolates will not be susceptible to this drug and additional resistance may develop in the future."

Dr. Sheppard added, "For superior sustained concentration levels, broad-spectrum activity, low toxicity and other factors discussed in this article, Iquix is an excellent choice for any significant ocular surface infection, particularly bacterial keratitis." CLS

To obtain references for this article, please visit http://www.clspectrum.com/references.asp and click on document #156.