Methicillin Resistant Staphylococcus aureus (MRSA) infections are currently a medical crisis of epidemic proportions throughout the world, specifically with a growing incidence of cutaneous infections such as impetigo and abscesses. Nitric oxide (NO) is a critical component of the natural host defense against pathogens such as MRSA, but its therapeutic applications have been limited by a lack of effective delivery options. To combat this deficit, a composite hydrogel/glass nanotechnology through which controlled, concentration- specific, gradual release of NO can be achieved, was investigated as a potential novel antimicrobial agent in an in vivo MRSA abscess model. The NOreleasing nanoparticles demonstrated antimicrobial activity against MRSA in vitro in cell cultures and in induced in vivo abscesses.

MRSA infection results in 12,000,000 outpatient/ emergency room visits and 400,000 hospital admissions annually in the US. MRSA is the number one pathogen isolated from soft tissue infections in US pediatric ERs. Evidence suggests that resistance is growing, leading clinicians to reduce their dependence on traditional antibiotics for management. First-line therapy is incision and drainage with adjunctive topical or systemic antibiotics added if necessary.1,2

Nitric oxide (NO) has emerged as a molecule of interest because its biological reactivity in the living system is diverse and extensive. Named “Molecule of the Year” by Science in 1992, NO's effects include: vascular tone and permeability, antioxidant, neurotransmission, immune function, angiogenesis, and modulation of wound healing. NO is antimicrobial and anti-inflammatory, as it is shown to modulate production and function of cytokines, chemokines, and growth factors.3,4

Despite these potential benefits, NO has not offered much clinical utility. Due to its high reactivity and short half-life, NO action and biological impact has been limited by the lack of suitable delivery systems.

Promising Developments
The development of Nitric Oxide nanoparticles represents a promising new development in this therapeutic area. NO nanoparticles are a novel composite material that combines the robust, malleable, and porous properties of silane-based solgel matrices with the thermal reduction potential of sugar glasses.5,6
Methods and Findings. MRSA abscesses were formed in the hind legs of female Balb/c mice. Seven animals were evaluated per group: NO nanoparticle treated, control nanoparticle treated, and no treatment. Single intralesional and two consecutive topical treatments of abscesses with the NO nanoparticles resulted in reduced abscess erythema/inflammation, size, and bacterial load clinically and histologically as compared to controls. Notably, pro- and anti-inflammatory cytokines that are involved in immunomodulation and wound healing were evaluated, revealing that NO-nanoparticles promoted a robust antimicrobial response ultimately resulting in accelerated host clearance of infection and healing of damaged tissues. (See Figures 1-2.7) For example, levels (in pg/mL; average +/- SEM) of TGF-β were 1349 +/- 1.51 for NO-treated abcesses, compared to 977 +/- 1.33 for controls and 911.76 +/- 3.38 for untreated. For MCP-1, the scores were 121.39 +/- 1.43, 19.56 +/- 0.35, and 36.54 +/- 0/95, respectively.

Together, these data suggest that the NO nanoparticles have the potential to serve as a novel class of topical therapy for the treatment of cutaneous infections.

—Ashish Bhatia, MD and Jeffrey T. S. Hsu, MD, Section Editors

Dr. Friedman is a resident physician at Albert Einstein College of Medicine, New York.

He has disclosed that PCT International Patent Application No. PCT/US2007/014442, entitled: Compositions For Sustained Release Of Nitric Oxide, Methods Of Preparing Same And Uses Thereof, (96700/1252) has been applied for.

Adapted from a presentation given at the Cosmetic Surgery Forum 2009, Las Vegas, NV, December 4-6, 2009 (