Every year, millions of cellulitis cases are reported in the United States, costing billions of dollars in ambulatory costs. Common treatments circulate antibiotics through the body using the bloodstream, which is a delivery system that requires large doses of antibiotics. Moreover, common treatments affect pathogenic and non-pathogenic bacteria alike, causing side effects such as nausea and diarrhea and promoting antibiotic resistance. We focused our research on developing NiSkin, a topical antibiotic that travels directly to the site of infection, providing better effectiveness with a smaller dose and avoiding common side effects.

Cellulitis: A Dermal Skin Infection

Cellulitis is a common dermal skin infection that accounts for more than 14 million cases, $3.7 billion in ambulatory care costs, and 650,000 hospitalizations in the United States annually [1]. Common symptoms include swelling, pain, and redness. If left untreated or treated incorrectly, cellulitis can spread to the lymph nodes and bloodstream and become life-threatening [2]. The primary treatment for cellulitis is oral beta-lactam antibiotics, such as cephalexin, for 5-7 days, targeting the primary pathogens - Group A Streptococcus and methicillin-sensitive Staphylococcus aureus [3,4].

Purulent cellulitis, a subtype of cellulitis, is characterized by the presence of fluid collection and abscesses along with other common symptoms [5,6,7]. Unlike nonpurulent cellulitis, predominantly caused by Streptococcus pyogenes, purulent cellulitis is caused by S. aureus, which accounts for 60-75 percent of abscess formation [8]. However, excessive antibiotic usage over several decades has led to the emergence of antibiotic-resistant S. aureus strains, such as methicillin-resistant S. aureus (MRSA) [4,9,10].

MRSA and Antibiotics Resistance

Methicillin-resistant S. aureus (MRSA) is recognized as a “serious threat” in CDC’s 2019 Antibiotic Resistance Threats Report [11]. According to the American Journal of Infection Control, skin and soft tissue infections (SSTIs) caused by MRSA have a significantly longer length of stay and greater mortality rate than non-MRSA cases [12]. With up to 70 percent of S. aureus SSTIs being MRSA [8], antibiotics with broader spectrum, such as trimethoprim sulfamethoxazole (TMP-SMX) and doxycycline, are prescribed for 5-10 days to treat purulent cellulitis [13].

However, oral antibiotics like cephalexin, TMP-SMX, and doxycycline come with adverse effects [14]:

Our Solution

Our solution combines nisin A and TD-1 to create a topical treatment that targets S. aureus and MRSA, while penetrating to the deepest site of the dermal infection and avoiding the adverse effects associated with oral or intravenous antibiotics.

How does our solution avoid side effects?

Using a topical treatment reduces side-effects caused by the systemic absorption of oral antibiotics. The advantages of topical treatments include localization, easy administration, minimized systemic absorption, and reduced toxicity and local irritation [15,16]. Oral antibiotics are the most common mode of drug delivery for cellulitis, because most topical antibiotics cannot pass through all the layers of the skin, including the stratum corneum. The stratum corneum, the uppermost layer of the skin, serves as one of the biggest barriers for many topical treatments due to its hydrophobic nature [15,16]. This nature is attributed to the stratum corneum’s structure, which consists of hydrophilic keratin-filled corneocytes tightly packed within hydrophobic lamellar lipids [16,17].

Transdermal drug delivery is an attractive alternative to oral antibiotics. Its delivery utilizes a painless, minimally invasive delivery system that involves drug diffusion through the layers of the skin into systemic circulation [18]. Different methods of transdermal drug delivery include chemical enhancement, microneedling, and electroporation [19]. Another way to pass through the layers of the skin is through combining a drug with a skin-penetrating peptide (SPP). TD-1 is an 11-amino acid SPP that has been shown to effectively facilitate transdermal delivery for large hydrophilic protein drugs through both co-administration and fusion [20,21].

What is effective against MRSA?

Antimicrobial peptides are a class of small peptides created by bacteria that have a wide range of inhibitory effects against bacteria, fungi, parasites, and viruses [22]. With the emergence of antibiotic-resistant organisms, antimicrobial peptides have shown promise in medicine, food, agriculture, and other fields. Specifically, bacteriocins are ribosomally synthesized antimicrobial peptides that have been gaining more traction [23]. Bacteriocins have been shown to be effective against a wide range of both Gram-positive and Gram-negative pathogens, having the potential to combat disease and infection [24]. Nisin A, a bacteriocin produced by Lactococcus lactis, has been shown to prevent the growth of antibiotic-resistant S. aureus, such as MRSA and vancomycin-intermediate S. aureus [25,26]. Nisin A is well-studied, FDA approved as a food additive, and generally regarded as safe [25]. It attacks pathogens by binding to the lipid II receptor on their membrane and initiating pore formation, leading to leakage of cell contents and rapid cell death [27,28].

What inspires us?

We were inspired to pursue a project that targets S. aureus in purulent cellulitis, because as antibiotic resistance rises in prevalence, antibiotics are no longer an effective treatment for a multitude of infections and diseases. Therefore, alternative measures need to be considered and implemented relatively soon to slow the rise of resistance or dissipate it altogether. We chose purulent cellulitis, because S. aureus is the primary pathogen causing the infection, and the infection ratio of MRSA to non-methicillin resistant S. aureus is increasing. Also, our delivery method being used to treat purulent cellulitis can be applied to other kinds of skin and soft tissue infections caused by MRSA. The implementation of bactericidal AMPs like nisin and the development of novel SPPs like TD-1 have encouraged us to fuse the peptides together into a single product that attacks MRSA lurking deep within the skin.


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