Antibacterial agent shows preclinical promise

Washington - The first in a new class of antibacterials has shown a high degree of in vitro potency in laboratory studies against key pathogens commonly associated with skin and soft tissue infections, as well as a low propensity for generating resistance in Staphylococcus aureus, according to its maker.

GlaxoSmithKline (GSK) submitted a new drug application for the experimental topical therapy retapamulin to the Food and Drug Administration (FDA) in November 2005 and expects to receive approval to market the product later this year.

In one study, researchers tested the susceptibility of a total of 3,486 clinical isolates gathered from patients with skin infections at 17 North American sites (nine in the United States, five in Canada and three in Mexico) against retapamulin.

"We found that retapamulin was the most active of all the compounds we looked at," says David Payne, Ph.D., director and head of GSK's microbiology department. "In this study, we also saw no strains that were resistant to our drug, although we saw strains that were resistant to many of the comparators. Overall, this demonstrates that retapamulin, because of its novel mechanism of action, has excellent in vitro activity against the key pathogens involved in skin and soft-tissue infections," he adds.

The molecule works by selectively inhibiting bacterial protein synthesis - more specifically, by binding to a unique site on the ribosome, Dr. Payne explains. "By virtue of binding to that site," he says, "it disrupts protein synthesis through a variety of different mechanisms" that are unique to the pleuromutilin class of compounds to which it belongs.

"Because no other drugs that are used in human medicine use that mechanism, there's a low likelihood of pre-existing target-specific resistance" to retapamulin, he adds. Accordingly, Dr. Payne says the company believes it's unlikely that the drug will encounter resistant isolates.

GSK researchers also have compared the potential for S. aureus to develop resistance to retapamulin and seven other commonly used antibacterial agents.

As part of the methodology for this study, Dr. Payne says, "We plated out a culture on high concentrations of retapamulin and counted the number of spontaneous resistant mutants that occurred on the plate."

Results here showed that retapamulin had a lower frequency of single-step resistance than all other topical antibiotics studied. In a similar multistep analysis, surviving mutants were still inhibited by concentrations of less than or equal to 2 μg/ml of retapamulin, representing the least elevation in MIC compared to other agents examined.

Dr. Payne says, "These studies have provided a very extensive evaluation, pushing retapamulin as hard as we can, to see what level of resistance can be created in a variety of different methods. The conclusion from this analysis is that retapamulin has a very low propensity to generate resistance, certainly lower than the other available topical antibiotics and many of the comparators we used in this study." This laboratory data indicates that retapamulin is unlikely to generate bacterial resistance when used clinically, he adds.

Preclinical in vivo testing, more over, has convinced GSK that retapamulin can be effective when used twice daily for only five days, Dr. Payne says.

"That confers some significant advantages over current therapeutic regimens, which are (three times a day) and dosed for longer than five days," he says.