SBIR-STTR Award

Staphylococcus aureus is the second leading cause of hospital-acquired bloodstream infections. In 2003, nearly 300,000 patients in US hospitals acquired an S. aureus infection, which accounted for nearly three million days of hospitalization, $9.5 billion in excess costs, and at least 12,000 inpatient deaths. Additionally, approximately 50% of the US population either persistently or intermittently carries a biofilm of S. aureus in their nose without experiencing any symptoms. Despite the lack of symptoms, nasal carriage of S. aureus is a well-known risk factor for developing a hospital-associated staphylococcal infection. Nasal carriers of S. aureus are three- to six-times more likely to acquire an S. aureus infection in the hospital, and, approximately 80% of the time, that infection is caused by the strain of S. aureus that lives in their nose. Based on infection rates and the prevalence of S. aureus nasal carriers, it has been estimated that eradicating S. aureus from the noses of surgical patients could save $4.5 billion a year in US hospital costs. The only FDA-approved treatment for nasal decolonization of S. aureus is 2% mupirocin. Clinical studies have shown that nasal decolonization decreases the number of infections contracted by S. aureus carriers, but resistance to mupirocin is becoming a concern. In vitro, the concentration of mupirocin required to inhibit growth of S. aureus increases significantly after only one exposure, and there is a growing body of clinical evidence linking mupirocin resistance to unsuccessful nasal decolonization. Nitric oxide, a free radical gas naturally produced by the human body to help fight infection, is a promising alternative to mupirocin for nasal decolonization of S. aureus. In recent years, the use of nitric oxide as an antimicrobial agent has been investigated due to its broad-spectrum antimicrobial activity, ability to diffuse directly through cell membranes, and the belief that it would be very difficult for nitric oxide-resistant strains of bacteria to develop. Additionally, nitric oxide has been shown to be effective against biofilm embedded bacteria. The goal of this SBIR project is to use Novan's proprietary nitric oxide-releasing technology to develop a topical nitric oxide-releasing nasal product capable of eradicating S. aureus biofilms from the noses of carriers without breeding bacterial resistance. In this proposal, Novan aims to: 1) Establish the minimum concentration of nitric oxide-releasing silica (Nitricil(tm)) required for bactericidal activity against 90% of S. aureus clinical isolates under planktonic and biofilm growth conditions in vitro;2) Determine whether S. aureus can develop stable resistance to nitric oxide;and 3) Evaluate the safety of Nitricil(tm) particles for use in the nose. Upon achieving these aims, Phase II efforts will focus on preclinical evaluation of intranasal Nitricil(tm) formulations, including: 1) testing the lead formulations against a mouse model of S. aureus nasal colonization;2) full preclinical toxicology;and 3) the quality scale-up manufacturing of both drug substance and drug product required to submit an Investigational New Drug application to the FDA.

Public Health Relevance:
Staphylococcus aureus infections cost US hospitals approximately $9.5 billion per year. Nasal carriage of S. aureus is a major risk factor for contracting such an infection, and estimates project that treatment to remove these bacteria from the noses of carriers could save $4.5 billion annually. The only FDA-approved treatment for nasal decolonization of S. aureus is mupirocin, but the prevalence of mupirocin-resistant S. aureus is increasing and is associated with treatment failure. The goal of this SBIR project is to use Novan's proprietary nitric oxide-releasing technology to develop a topical nasal product capable of eradicating S. aureus biofilms from the noses of carriers without breeding bacterial resistance.

Thesaurus Terms:
Accounting;Bacteria;Bacteria Resistance;Bacteria Resistant;Bacterial Resistant;Bactroban;Belief;Breathing;Breeding;Cell Membrane;Cessation Of Life;Clinical;Clinical Research;Clinical Study;Common Rat Strains;Contracting Opportunities;Contracts;Cristobalite;Cytoplasmic Membrane;Death;Development;Diffuse;Dose;Drug Formulations;Drug Precursors;Drug Resistance;Drugs;Endogenous Nitrate Vasodilator;Endothelium-Derived Nitric Oxide;Fda Approved;Formulation;Free Radicals;Gases;Gel;Generalized Growth;Genetics-Mutagenesis;Goals;Growth;Hospital Costs;Hospitalization;Hospitals;Human Figure;Human Body;In Vitro;Infection;Inhalation;Inhaling;Inpatients;Investigational New Drug Application;Killings;Lead;Link;Measures;Medication;Microbial Biofilms;Modeling;Mononitrogen Monoxide;Mupirocin;Mutagenesis;Mutagenesis Molecular Biology;Nasal;Nasal Passages Nose;Nitric Oxide;Nitric Oxide Donors;Nitrogen Monoxide;Nitrogen Protoxide;Nose;Operative Procedures;Operative Surgical Procedures;Patients;Pb Element;Pharmaceutic Preparations;Pharmaceutical Preparations;Phase;Plague;Plasma Membrane;Population;Prevalence;Pro-Drugs;Problem Solving;Prodrugs;Pseudomonic Acid;Rat;Rats Mammals;Rattus;Research;Resistance;Resistance Development;Resistant Development;Respiratory Aspiration;Respiratory Inspiration;Respiratory System, Nose, Nasal Passages;Risk;Risk Factors;S. Aureus;S.Aureus;Sbir;Sbirs (R43/44);Safety;Sand;Sepsis;Serial Passage;Silica;Silicon Dioxide;Small Business Innovation Research;Small Business Innovation Research Grant;Spinal Column;Spine;Staphylococcal Infections;Staphylococcus Aureus;Staphylococcus Infection;Surgical;Surgical Interventions;Surgical Procedure;Symptoms;Technology;Testing;Therapeutic;Time;Tissue Growth;Toxic Effect;Toxicities;Toxicology;Treatment Failure;Tridymite;Vertebral Column;Work;Yersinia Pestis Disease;Anti-Microbial;Anti-Microbial Agent;Anti-Microbial Drug;Antimicrobial;Antimicrobial Agent;Antimicrobial Drug;Backbone;Bacterial Resistance;Bactericidal;Bactericide;Base;Biofilm;Bloodstream Infection;Cost;Developing Resistance;Developmental;Drug Development;Drug Resistant;Drug/Agent;Endothelial Cell Derived Relaxing Factor;Experience;Fighting;Heavy Metal Pb;Heavy Metal Lead;In Vivo;Inspiration;Irritation;Manufacturing Scale-Up;Mouse Model;Ontogeny;Particle;Plasmalemma;Pre-Clinical;Preclinical;Preclinical Evaluation;Resistance Strain;Resistance To Bacteria;Resistance To Bacterial;Resistance To Drug;Resistant;Resistant Strain;Resistant To Bacteria;Resistant To Bacterial;Resistant To Drug;Small Molecule;Success;Surgery

Staphylococcus aureus is the second leading cause of hospital-acquired bloodstream infections. In 2003, nearly 300,000 patients in US hospitals acquired an S. aureus infection, which accounted for nearly three million days of hospitalization, $9.5 billion in excess costs, and at least 12,000 inpatient deaths. Additionally, approximately 50% of the US population either persistently or intermittently carries a biofilm of S. aureus in their nose without experiencing any symptoms. Despite the lack of symptoms, nasal carriage of S. aureus is a well-known risk factor for developing a hospital-associated staphylococcal infection. Nasal carriers of S. aureus are three- to six-times more likely to acquire an S. aureus infection in the hospital, and, approximately 80% of the time, that infection is caused by the strain of S. aureus that lives in their nose. Based on infection rates and the prevalence of S. aureus nasal carriers, it has been estimated that eradicating S. aureus from the noses of surgical patients could save $4.5 billion a year in US hospital costs. The only FDA-approved treatment for nasal decolonization of S. aureus is 2% mupirocin. Clinical studies have shown that nasal decolonization decreases the number of infections contracted by S. aureus carriers, but resistance to mupirocin is becoming a concern. In vitro, the concentration of mupirocin required to inhibit growth of S. aureus increases significantly after only one exposure, and there is a growing body of clinical evidence linking mupirocin resistance to unsuccessful nasal decolonization. Nitric oxide, a free radical gas naturally produced by the human body to help fight infection, is a promising alternative to mupirocin for nasal decolonization of S. aureus. In recent years, the use of nitric oxide as an antimicrobial agent has been investigated due to its broad-spectrum antimicrobial activity, ability to diffuse directly through cell membranes, and the belief that it would be very difficult for nitric oxide-resistant strains of bacteria to develop. Additionally, nitric oxide has been shown to be effective against biofilm embedded bacteria. The goal of this SBIR project is to use Novan's proprietary nitric oxide-releasing technology to develop a topical nitric oxide-releasing nasal product capable of eradicating S. aureus biofilms from the noses of carriers without breeding bacterial resistance. In this proposal, Novan aims to: 1) Establish the minimum concentration of nitric oxide-releasing silica (Nitricil(tm)) required for bactericidal activity against 90% of S. aureus clinical isolates under planktonic and biofilm growth conditions in vitro;2) Determine whether S. aureus can develop stable resistance to nitric oxide;and 3) Evaluate the safety of Nitricil(tm) particles for use in the nose. Upon achieving these aims, Phase II efforts will focus on preclinical evaluation of intranasal Nitricil(tm) formulations, including: 1) testing the lead formulations against a mouse model of S. aureus nasal colonization;2) full preclinical toxicology;and 3) the quality scale-up manufacturing of both drug substance and drug product required to submit an Investigational New Drug application to the FDA.