It is widely recognized that overuse of antibiotics has played a profound role in the emergence and dissemination of drug-resistant bacteria, and has often been blamed for the spread of these so-called superbugs. In the U.S., virulent strains of methicillin-resistant Staphylococcus aureus (MRSA), a predominant cause of community-acquired skin and soft tissue infections, are of urgent public health concern given the rapid spread of highly drug-resistant strains such as MRSA-USA300.
Government bodies and health organizations are now formally recognizing the urgent need for new generations of antimicrobial agents that are fast-acting and effective against drug-resistant bacteria. In order to be effective, these new drugs must minimize the possibility that bacteria could develop resistance.
In a study published in Emerging Infectious Diseases, scientists from Japan reported data suggesting a role for over-the-counter (OTC) topical antibiotic ointments, which are used frequently in the U.S., in aiding the spread of MRSA-USA300. Triple-antibiotic ointments such as Neosporin often contain the active drugs bacitracin and neomycin. The study, which analyzed greater than 250 clinical isolates of MRSA from Japan and Korea, found that while this drug combination was effective against many strains of MRSA, the drugs were shown to be largely ineffective against the virulent MRSA-USA300 strains.
Based upon the relationship between the prevalence of MRSA-USA300 in Japan and Korea and the usage of OTC drugs (both of which are relatively low compared to the U.S.), the study concluded that the selective pressure applied by indiscriminant use of OTC antibiotics could be responsible (at least in part) for the rapid dissemination of MRSA-USA300.
AgaDerm (NVC-422 Gel) represents a new class of topical anti-infectives known as Aganocides®, which were designed by NovaBay Pharmaceuticals, Inc., to mimic the body’s natural defense against infection. Through a differentiated mechanism of action, Aganocides have been shown to be broadly effective against both Gram-positive and Gram-negative pathogens, and were proven safe and well tolerated in human clinical trials.
AgaDerm is in Phase 2 clinical development for treating impetigo, a highly contagious skin infection affecting children worldwide, which is caused by Staphylococcus aureus, including MRSA, Streptococcus pyogenes, or both. In a clinical study, AgaDerm demonstrated a 100 percent response rate for treating patients with impetigo caused by MRSA, whether MRSA was the sole organism or in a mixed infection. The study, which was published recently in the International Journal of Clinical and Experimental Pathology, also tested NVC-422 against 55 recent clinical isolates of MRSA acquired from a database of patients in the U.S. and Europe, where MRSA-USA300 is more prevalent. Again, NVC-422 was shown to be rapidly bactericidal against all bacterial isolates, regardless of resistance phenotype. Although the scope of the study did not specifically identify MRSA sub-types, it is very likely that the USA300 clone was represented in this population.
This initial evidence is very encouraging, as it suggests that AgaDerm may be effective against clinically relevant strains of MRSA that are not well controlled by current therapies.
In stark contrast to traditional antibiotics, AgaDerm’s unique mechanism of action is not specific to one, or even a small group of molecular targets, making it extremely difficult for bacteria to become naturally resistant. In a poster presented by NovaBay earlier this year at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), NVC-422 was shown to maintain its antimicrobial activity against a number of important human pathogens, including MRSA, in a serial passage study. The study examined the activity of NVC-422 under laboratory conditions that promote the evolution of bacterial resistance. After 50 passages, the minimum inhibitory concentration (MIC) of NVC-422 against MRSA did not change, indicating that the bacteria do not appear to develop resistance over time.
The basis for this perhaps lies in the mechanism of action of Aganocides relative to drugs like bacitracin and neomycin. Neomycin belongs to a class of antibiotics known as aminoglycosides, which have relatively weak activity against Gram-positive bacteria such as MRSA. Resistance to neomycin is common among strains of MRSA and the Japanese study was consistent with these earlier findings. Bacitracin is a highly potent drug that acts by disrupting the assembly of the bacterial cell wall through inhibition of a single pathway. However, bacteria that develop the ability to either pump bacitracin outside of the cell or restore the target pathway using alternative cellular machinery quickly become resistant to bacitracin.
AgaDerm has the potential to become an alternative to traditional topical antibiotics like neomycin and bacitracin, which are used commonly in the U.S. to treat soft tissue infections. As the recent study has shown, overuse of these products may inadvertently promote dissemination of highly drug-resistant MRSA due to their inability to eliminate the most dangerous strains. AgaDerm was not only effective at killing virulent strains of MRSA, but also demonstrates a significantly reduced risk of promoting drug resistance, compared to other antibiotics.