Rx Perspective

New Antibiotic Offers Highest Concentration

Levofloxacin 1.5% offers advantages in three critical areas: potency, persistence and penetration.

By Thomas John, M.D.

Fluoroquinolones can be divided into two groups: Those effective against predominantly gram-negative bacteria (ciprofloxacin [Ciloxin, Alcon] and those effective against both gram-negative and gram-positive bacteria (gatifloxacin [Zymar, Allergan], levofloxacin 1.5% [IQUIX, Vistakon Pharmaceuticals] and moxifloxacin [Vigamox, Alcon]). In this article, I'll refer to this latter group as "newer-generation" fluoroquinolones.

In deciding which of the ophthalmic fluoroquinolones to use in any given case, we want to know how well the drug works (potency), how long it stays in the eye (persistence) and whether it gets to where it needs to be (penetration). In each of these areas, I feel that the new high-concentration antibiotic, levofloxacin 1.5%, offers advantages.

Potency

Whether we are talking about blepharitis, conjunctivitis, keratitis or endophthalmitis, the majority of ocular infections are caused by gram-positive organisms. Although gram-negative organisms are less common, they can be devastating. For example, Pseudomonas aeruginosa, commonly associated with contact lens-related corneal infections, can perforate the cornea in as little as 48 hours. It is imperative, therefore, to have broad-spectrum coverage against both gram-negative and gram-positive bacteria.

Figures 1 and 2 show that newer generation fluoroquinolones have similar susceptibility patterns in vitro, according to the Ocular Trust 2 database.

The latest data released from Ocular TRUST (Tracking Resistance in the United States), a large national database of ocular isolates that have been centrally tested against a variety of antibiotics in vitro, shows that the newer-generation fluoroquinolones have virtually identical susceptibility patterns (Figures 1, 2)¹. All three are highly effective against Streptococcus pneumonia, Haemophilus influenzae and methicillin-susceptible strains of Staphylococcus aureus (MSSA) and Staphylococcus epidermidis. The methicillin-resistant strains of S. aureus (MRSA) and S. epidermidis have unfortunately shown high degrees of resistance to most ophthalmic antibiotics.

The "area under the concentration-time curve" (AUC) is a measure of drug exposure. Bacterial eradication and clinical cure correlate with the AUC to MIC (minimum inhibitory concentration) ratio. Our goal in treating infectious organisms is to achieve the maximum drug exposure or AUC that we can. We often talk about efficacy in terms of exceeding the minimum inhibitory concentration required to inhibit the growth of 90% of the bacteria (MIC90). In reality, of course, we want to kill all the bacteria so they cannot replicate or mutate. In this regard, we should recognize the very high concentration of IQUIX in the tears — hundreds of times higher than the MIC90 levels for common ocular pathogens.

Following a single two-drop dose of levofloxacin 1.5%, tear concentrations in humans have been shown to peak very quickly, within 15 minutes (Figure 3)². Although IQUIX was not studied or approved for pre- or post-surgical indications, for short-duration procedures like cataract surgery, it is very important to be able to reach maximum concentration on the ocular surface quickly so that we can kill pathogens before they enter the eye.

Persistence

The same graph of tear concentrations (Figure 3), shows that the high concentrations of levofloxacin 1.5% continue over time. Six hours after instilling a dose of IQUIX, levofloxacin levels are still about 200 μg/mL, which is 400 times the MIC90 of S. aureus, 200 times that of S. epidermidis, 100 times that of S. pneumonia and 50 times that of P. aeruginosa. So even 6 hours later, one can be fairly confident the bugs are going to be eradicated.

All of the fluoroquinolones act on both enzymes needed for bacterial replication, DNA gyrase and topoisomerase IV. For the most part, this two-pronged approach helps prevent the development of resistance. But it also means that the drug kills bacteria only when they are actively replicating. We need the antibiotic to persist long enough to keep killing bacteria as some segments die and others begin to replicate, until eventually the entire pool of bacteria is eradicated.

Penetration

Persistence in the tears is important, especially when treating a known infection. But for many ophthalmic applications, we want to know whether the antibiotic can penetrate beyond the tears into the cornea and anterior chamber.

Figure 3 demonstrates that IQUIX concentrations peak within 15 minutes and continue at high concentrations over time.

In rabbit studies, the highly concentrated dose of levofloxacin penetrated the corneal tissue quickly. Total drug exposure or AUC was 18.2 for IQUIX. Excellent corneal concentration is still not good enough for the cataract surgeon hoping to prevent endophthalmitis. In this case, we want the drug to penetrate to the aqueous humor. In the same rabbit study, IQUIX remained in the aqueous for up to 12 hours, with a mean AUC of 2.7.

Such levels of penetration and concentration should give us great comfort in using IQUIX over existing fluoroquinolones for either corneal infection or for ocular surgical prophylaxis.

Other Factors

The "Three Ps" I've discussed are the most important factors in choosing a topical antibiotic, but there are other considerations. Ideally, we want a drug with as little toxicity to the cornea as possible. In one recent in vitro study, researchers cultured human keratocytes, which are important for corneal stroma and wound healing, and endothelial cells, which play a role in the clarity of the cornea. The cells exposed to levofloxacin did not cause any toxicity for one hour.⁴

In rabbits and monkeys with corneal abrasion, treatment with IQUIX caused no adverse effects in re-epithelialization, keratocyte structure or organization, or wound healing. ⁵ This is an important consideration when using topical antibiotics as prophylaxis in corneal refractive surgery, where smooth, rapid epithelial healing is critical.

Ophthalmic Research Associates recently showed no change in endothelial cell density, cell morphology or central corneal thickness in the eyes of healthy volunteers who used levofloxacin 1.5% intensively (224 drops) over a 2-week period.⁶

Finally, the antibiotic works only when the patient uses it. IQUIX has a near-neutral pH of 6.5. It is preservative free, so it does not cause the stinging we sometimes associate with benzalkonium chloride. In my experience, it has been well tolerated, even when dosed every 15 minutes.

Conclusions

IQUIX is the first newer-generation fluoroquinolone approved for the treatment of corneal ulcers. Particularly when a gram stain shows the infection to be gram-negative, clinicians should consider levofloxacin 1.5% for preventing a potentially fast-moving Pseudomonas infection from causing lasting damage. Similarly, good coverage of gram-positive organisms is provided by Iquix. Culture results continue to be important, especially in serious, sight-threatening infections, and if MRSA is known or suspected, one should add another antibiotic based on the sensitivity results and follow the patient closely.

Given the evidence cited, IQUIX is my first choice among topical ophthalmic antibiotics for corneal ulcers and many other circumstances where a newer-generation fluoroquinolone is warranted. With such a high concentration of levofloxacin, I am confident that we can completely eradicate bacteria and therefore, at least theoretically, have less chance of developing resistance to the drug over time. OM

Dr. John is a speaker for Vistakon Pharmaceuticals, Alcon, Allergan, ASICO, Bausch & Lomb, Bio-Tissue, Inspire, Marco, Moria, and Nidek. He has also provided consulting services to Vistakon Pharmaceuticals. He has no direct financial interest in any of the products mentioned in this article.

References

1. McDonnell PJ, Sahm DF. Longitudinal nationwide surveillance of antimicrobial susceptibility in ocular isolates (Ocular TRUST 2). American Academy of Ophthalmology 2007 annual meeting, Poster PO052.
2. Walters TR, Hart W. Tear concentration of 1.5% levofloxacin ophthalmic solution following topical administration in healthy adult volunteers. Invest Ophthalmol Vis Sci 2003;44:E-Abstract 445.
3. McDonald MB. Research review and update: IQUIX (levofloxacin 1.5%). Int Ophthalmol Clin 2006;46:47-60.
4. Skelnik DL, Clark LA, Bezwada P. Effect of drug concentration and exposure time of levofloxacin, ofloxacin, ciprofloxacin, gatifloxacin, and moxifloxacin on human corneal endothelial cells and keratocytes. Invest Ophthalmol Vis Sci 2003;44:E-Abstract 4739.
5. Clark L, Bezwada P, Hosoi K, et al. Comprehensive evaluation of ocular toxicity of topical levofloxacin in rabbit and primate models. J Toxicol Cutan Ocul Toxicol 2004;23:1-18.
6. Data on file, Vistakon Pharmaceuticals, LLC