There has been a lot of talk about how some bacteria are becoming resistant to our strongest therapeutic agents. This is critical as we battle the ever more potent pathogens we see in infectious keratitis.
Powerful Agents
Fluoroquinolones were first introduced in 19851 and have been extremely effective in fighting infections. They bind to and disrupt the activity of two enzymes these bugs need for DNA replication: DNA gyrase and topoisomerase IV. This prevents the bacterial DNA from super-coiling, a process that enables repair and replication.
The low incidence of toxicity and allergic reaction, and the fact that fluoroquinolones achieve some of the highest aqueous humor concentrations when applied topically,2 has allowed them to become the powerhouse drug for severe ocular infections such as endophthalmitis, blebitis and keratitis.
While research has shown emerging fluoroquinolone resistance, there has also been research on new formulations that can help us win the battle of the bugs.
Research on Resistance
One study looked at emerging fluoroquinolone resistance in bacterial keratitis over the past five years.3 The authors reviewed 1,053 ocular isolates of bacterial keratitis presenting to their laboratory over four years. They noticed two trends: the incidence of bacterial keratitis in general had decreased each year; and resistance of Staphylococcus aureus to ciprofloxacin and ofloxacin had increased from about 5% to 35%.
They also showed that the most resistant bacteria were streptococcal and coagulase-negative staphylococcal species. The gram-negative bacteria continued to show good susceptibility.
A more recent study looked at 454 hospital cases in Austria.4 The researchers took isolates of each keratitis that presented and compared susceptibility to 10 ocular antibiotics. They found chloramphenicol to be the most effective, but this drug is seldom used in the West due to cases of aplastic anemia and “gray baby” syndrome.5 The most effective drugs available to physicians in the United States were the fluoroquinolones (this paper studied ciprofloxacin and ofloxacin). However, the study showed that when fluoroquinolones were not effective, the offending bacteria were coagulase-negative staphylococcal and streptococcal viridae.
Another study observed the actual mutation Streptococcus pneumoniae make as they build resistance over a series of applications. This study isolated the mutant strains and recolonized them.6 Although this experiment was in vitro, there is much evidence and many studies that show resistance to fluoroquinolones at the clinical level as well.
New Modifications
Michael S. Osato, Ph.D., of the Baylor College of Medicine led a study that claims that metal ions in the ocular fluids may significantly decrease the bioavailability of fluoroquinolones.7 The ionic state of BSS, the surgical solution that mimics human tissue fluid, is similar to that of the eye, particularly the aqueous. Dr. Osato surmised that BSS decreased the susceptibility of ciprofloxacin more than ofloxacin.
Another study out of the University of California-Los Angeles showed that varying the pH also had a significant effect on a fluoroquinolone’s absorption rate.8 At 7 pH, which closely resembles that of tears, the absorption rate of levofloxacin is highest, followed by ofloxacin and then ciprofloxacin. By slightly modifying the solubility of pH, mechanism of action or effect at various ionic states, new fluoroquinolones can increase the susceptibility of these key microorganisms.
Levofloxacin (Quixin) has a slight modification in its chemical structure that utilizes the L-isomer. This may have a greater affinity to affecting gram-positive bacteria that have shown resistance, and gives the medication a higher absorption rate at 7 pH.
Sparfloxacin and gatifloxacin have also shown promise against gram-positive bacteria, but are not yet available. Higher concentrations of medications beyond 0.5% or 0.3% are under investigation. In a study that measured the pharmacokinetic data of all oral fluoroquinolones, results showed that these drugs interact with cation-containing products. If taken with iron compounds, their bioavailability decreases more than 50%. This is particularly true with ciprofloxacin and moxifloxacin.
Theophyline had a drug-drug interaction with enoxacin, perfloxacin and ciprofloxacin; sparfloxacin had a higher phototoxicity potential.9 Of course, oral medications have a different absorption rate and concentration profile than topical drugs, so these studies may not translate for ocular use.
Although the newer fluoroquinolones show great promise, another study indicated that bacteria such as Strep. pneumoniae could show cross-resistance.10 By looking at the chromosome sequence of this major human pathogen, Strep. pneumoniae can mutate the intracellular targets of the fluoroquinolone—DNA topoisomerase gyrase and topoisomerase IV. There has been a lot of talk about how some bacteria are becoming resistant to our strongest therapeutic agents. This is critical as we battle the ever more potent pathogens we see in infectious keratitis.
Advances in fluoroquinolones will raise the likelihood of destroying harmful pathogens, but bacteria will find ways to mutate and resist their onslaught. The battle for new ways of treating pathogens is never-ending.
Dr. Karpecki is on the speaker’s bureau or optometric advisory board for Allergan, Santen and Alcon.
