Promise of Nitric Oxide for Skin and Soft Tissue Infections

Stagnation in the development of new antimicrobial agents, poor antimicrobial stewardship practices, and at times indiscriminate use of antimicrobial agents have created a perfect storm in which multidrug-resistant infections have flourished in hospital and community settings. The increasing resistance to various anti-infective agents by bacteria and fungi—in particular Staphylococcus aureus, which is responsible for the majority of skin infections—is of particular concern and presents increasing challenges in treating skin and soft tissue infections (SSTIs).^1,2 The need for new treatments for SSTIs “is very urgent as several bugs are now resistant to many of the anti-infective agents we have,” said Leon Kircik, MD, clinical associate professor of dermatology at the Icahn School of Medicine at Mount Sinai, in New York City. Any new treatment must not only meet the criteria of efficacy against bacterial and fungal infections, but also overcome the development of resistance.

Over the past several decades, there has been growing interest in nitric oxide (NO) for the treatment of skin infections. This ubiquitous endogenous free radical traverses most physiologic barriers and plays a variety of roles, including blood pressure regulation, neurotransmission, inhibition of platelet aggregation, and regulation of immune response. Nitric oxide is involved in the maintenance of the protective barrier against microorganisms and is a critical component of the natural host defense mechanism against a broad spectrum of pathogens.¹ Through its modulation of cytokines and known roles in angiogenesis, collagen deposition, and keratinocyte proliferation, NO also plays a critical role in the various phases of wound healing.^1,3

The application of NO as an anti-infective agent has been gaining momentum. Despite its challenges as a free radical with a short half-life and high reactivity, the physiological properties of NO have several advantages that include broad-spectrum, multifaceted antimicrobial activity with potential to minimize the development of resistance. In addition, the ability of NO to diminish bacterial burden and accelerate wound healing presents an attractive therapeutic option to the current challenges of increasing resistance to anti-infective agents. “The risk of bacterial resistance to both innate production and exogenous delivery of NO is minimized because NO exhibits multiple mechanisms of antimicrobial action both by inhibiting cell growth and by directly killing the pathogen,” said Adam Friedman, MD, FAAD, associate professor of dermatology at George Washington School of Medicine and Health Sciences, in Washington, DC. Consequently, translating this free radical from the bench to the bedside is an area of active clinical investigation. Several studies are ongoing to evaluate the application of NO as a broad-spectrum antimicrobial agent against Gram-positive and Gram-negative bacteria, as well as fungal agents and parasites.^1,3-5

The key challenge, however, is that in its natural state, NO is highly reactive and unstable, and its clinical utility is limited. “The limitation to date with respect to the clinical use of NO has not been the number of potential applications, as these are practically limitless,” said Dr Friedman, adding “rather, it has been the development of a practical, safe, and translatable delivery system for NO, as this extraordinary biomolecule is reactive and short-lived under physiological conditions.” Several NO delivery platforms have been evaluated for topical application, including acidified nitrate, diazeniumdiolates, nanoparticles, probiotic patch, S-nitrosothiols, and NO-metal complexes.^3,6 Although these NO delivery models have their advantages and limitations, they provide evidence for the potential clinical application of NO-based topical therapy.¹

The development of a nanotechnology platform provides a versatile option for the delivery of drugs across lipophilic barriers that have been traditionally challenging to cross by many therapeutic agents.⁷ Specifically, NO-releasing nanoparticles (NO-np) provide a platform for generating powder formulations of NO that is sufficiently stable to be used topically. This platform allows versatility because the release rate and total concentration of NO delivered from the NO-np to the affected area can be modulated by altering the production method of the nanoparticles. Nitric oxide-releasing particles have now been extensively studied for the treatment of acne.^4,8 “Some of the ongoing trials are in early phase while others are in late phase clinical development, although it will take several more years before we see a clinical application,” said Dr Kircik. The clinical application of NO has also been investigated for the treatment of SSTIs, and studies in animal models show positive results for the treatment of infections caused by Candida albicans, Pseudomonas aeruginosa, and methicillin-resistant S aureus.^3,6,9 These studies suggest that NO-np may have the potential to serve as a novel topical anti-infective agent that can be used for the treatment of SSTIs.

The potential of this emerging class of topically applied anti-infective agents is significant. Slow-release formulations can allow steady and constant penetration into the infected wound, unlike current formulations that have an initial peak without extended release of the drug. In addition, the lack of systemic toxicity; the potential to use as monotherapy, bridge, or in combination with other systemic treatment depending on the clinical indications; as well as the lack of demonstrated resistance to micobicidal activity present NO as a very attractive treatment option for skin infections.^1,3 The key advantages of NO-based treatment, according to Dr Kircik, are the lack of antibacterial resistance and a good adverse effect profile. While the application of NO for the treatment of SSTIs continues to be evaluated with a variety of delivery platforms, it is important to heed Dr Kircik’s caution that it will take several more years before it is available in the clinic.

References

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5. Kutner AJ, Friedman AJ. Use of nitric oxide nanoparticulate platform for the treatment of skin and soft tissue infections. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2013;5(5):502-514.
6. Del Rosso JQ, Kircik LH. Spotlight on the use of nitric oxide in dermatology: what is it? What does it do? Can it become an important addition to the therapeutic armamentarium for skin disease? J Drugs Dermatol. 2017;16(1):s4-s10.
7. Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015; 33(9): 941-951.
8. Baldwin H, Blanco D, McKeever C, et al. Results of a phase 2 efficacy and safety study with SB204, an investigational topical nitric oxide-releasing drug for the treatment of acne vulgaris. J Clin Aesthet Dermatol. 2016;9(8):12-18.
9. Macherla C, Sanchez DA, Ahmadi MS, et al. Nitric oxide releasing nanoparticles for treatment of Candida albicans burn infections. Front Microbiol. 2012;3:193.