Iasis Molecular Sciences and Novion Technologies are presently seeking A-Round investment. The problems that we are addressing (discussed below) are documented to burden health care systems around the globe to the tune of billions of dollars annually. The absence of “alternate” near-term solutions to these problems will provide the investor with a respectable business opportunity. Interested parties are encouraged to contact Dr. Vachon.
HEALTHCARE-ASSOCIATED INFECTIONS (HAIs)
HAIs are estimated to occur in 5% of all hospitalizations in the U.S., resulting in extended hospital stays, increased mortality, and added healthcare costs (1,2). Microorganisms can (essentially) reside on any surface within the clinical environment, thus raising the patient’s risk for transmission of infection. In 2002, an estimated 1.7 million healthcare-associated infections occurred in the U.S. leading to 99,000 deaths (3). In March 2009, the CDC released a report estimating overall annual direct medical costs of healthcare-associated infections that ranged from $28-$45 billion (4-6). It is also worth noting that Medicare no longer will reimburse hospitals for treating vascular catheter-associated infections that develop during a patient’s stay, causing hospitals to absorb additional financial losses.
Invasive supportive measures such as: (1) endotracheal intubation, (2) intravascular lines, and (3) urinary catheters involve the use of devices fabricated from medical elastomers. The surfaces of these devices provide the nidus for the formation of bacterial biofilm and subsequent biofilm-associated infection (7-15). Once established, biofilms are extremely difficult to treat using standard approaches such as antimicrobial drugs. As a consequence, removal of implants is frequently necessitated. Such an occurrence significantly increases the risk of morbidity, mortality, and healthcare costs. Prevention strategies based on the modification of the biomaterial or its surface so as to discourage microbial adhesion and biofilm formation is an approach that has gained increasing attention over the last several years. Such methods have included: surface modifications including coating the surface antimicrobial agents. However, it is important to note that such strategies have the potential to impact tissue integration (if desired), blood compatibility, or may result in an allergic response by the patient depending upon the agents added to the device(s) or the methodology used for incorporation.
A major shortcoming with almost all indwelling devices treated with antimicrobial coatings is that they provide effective protection for only a limited time. For example, antiseptic or antimicrobial impregnated urinary catheters have been studied extensively as an adjunctive measure for preventing catheter associated urinary tract infections (16-17). Currently available antimicrobial urinary tract catheters are typically coated with silver alloys, nitrofurazone, minocycline, or rifampin. Silver alloy catheters and antibiotic impregnated catheters have been demonstrated to significantly reduce the incidence of asymptomatic bacteriuria in adult patients catheterized less than 7 days. However, for duration of catheterization greater than 7 days, the reduction in asymptomatic bacteriuria was less pronounced (9,18,19). The inability of most current indwelling devices to provide long-term protection is largely a reflection that antimicrobials are applied simply as a coating and thus are susceptible to relatively rapid depletion. Another limitation of many indwelling devices treated with antimicrobials is that they are not uniformly effective against the range of gram positive and gram-negative bacteria and mycotic organisms that are frequently encountered.
INNOVATION: Iasis Molecular Sciences (IMS) has developed a family of Multi-component Active Additives (U.S. & foreign patents pending) with the capability of delivering a variety of active agents from a variety of materials. These additives can be readily formulated into a variety of thermoplastic and thermosetting medical and industrial materials as well as into lacquers and emulsions for coating and painting surfaces. The particular chemistry employed in the synthesis of these additives minimizes many of the process limitations that can be encountered when adding active pharmaceutical ingredients to medical or industrial materials including degradation, phase changes, and cosmetic irregularities. In addition, the technology enables the converter/formulator with the capability to readily incorporate one or more active agent(s) into a single material thus facilitating the preparation of materials that possess more than one mechanism of killing pathogenic microbes.
More recently, acrylic latex paints incorporating low weight percentages (~1.0-2.0 wt%) of our additives have demonstrated high levels of disinfection (> 4-logs) against a broad spectrum of bacterial and fungal pathogens. We anticipate that the low toxicity of our solution favors their use within indoor environments that may not benefit from paints incorporating static agents such as zinc pyrithione. Coating applications beyond decorative interior paints include commercial and residential building coatings, coatings for industrial (and non-industrial) conduits that carry gases, air, and/or a variety of fluids and are susceptible to bacterial or fungal colonization and/or biofilm-mediated corrosion, and marine coatings where aquatic fouling is a significant complication.
Diabetes occurs in over 8% of persons 20 years of age and older (24 million persons in the U.S.A. alone) (20). Of these, approximately 15–25% will develop a foot ulcer in their lifetime (21). Disruption of the normal inflammatory/healing process can result with diabetes and lead to a non-healing phenotype. In normal healing, inflammation is orderly and controlled for the different phases of wound repair allowing resolution to proceed in a uniform fashion. In non-healing diabetic wounds, the non-healing phenotype is frequently manifested by an elevated inflammatory response and by the inability to proceed to resolution of inflammation. Both type 1 and type 2 diabetics exhibit elevated levels of circulating pro-inflammatory cytokines and reduced levels of anti-inflammatory cytokines (22;23). Diabetic wounds themselves are characterized by a delay in inflammatory cell influx that is then, followed by a state of chronic inflammation (22;23) and in many cases further complicated by bacterial burden.
All wounds are to some degree colonized by microorganisms. Replicating microorganisms within a wound can have a detrimental effect characterized by progressive wound breakdown or by a wound that has not progressed toward healing after previously showing signs of progress. Diabetes significantly increases the risk of infection greatly complicating treatments and increasing the time to resolution (24). Foot infections are the most common problems in persons with diabetes and diabetics are predisposed to foot infections as a consequence of a compromised vascular supply secondary to diabetes. Local trauma and/or pressure with the underlying complexity of microvascular disease can contribute to diabetic foot ulceration and subsequent wound infection. Foot infection in the diabetic ranges from simple superficial cellulitis to chronic osteomyelitis which can lead to amputation. Infections in patients with diabetes are difficult to treat with systemic antibiotic therapy because these patients have impaired microvascular circulation, which limits the concentration of antibiotics in the infected tissues. Simple foot infection (cellulitis) is the most easily treatable and reversible form of foot infection in patients with diabetes. Generally, Staphylococcus aureus and group A streptococci the most likely invading pathogens (25-27). Deep skin and soft tissue infections are generally associated with gram negative bacilli such as Escherichia coli, Pseudomonas aeruginosa, or Klebsiella pneumoniae, but are generally curable unless the infection is the result of a multi-drug resistant organism (MDRO).
Chronic osteomyelitis in patients with diabetes mellitus is the most difficult infection to cure. Adequate surgical debridement, in addition to oral and topical antimicrobial therapy is, at a minimum, required for treatment and cure. In many cases the cure is surgical removal of the infected bone. It is estimated that as many as 65% of all patients with infected diabetic foot ulcers contract osteomyelitis (28). 14–24% of persons with diabetic foot ulcers will have an amputation (American Diabetes Association, 1999). Complications associated with foot ulcers account for 20–25% of all hospital days among persons with diabetes (29). The economic burden associated with the treatment of diabetic foot ulcers is enormous with treatment in the United States estimated to be many billions of dollars annually (29). Coupled with aging, diabetes is driving the explosive increase (10% annually) in wound care costs. It is clear that “despite the important medical advances that have been made in the treatment of diabetic foot ulcers in the past fifty years, there remains a significant need for more effective therapies” (30).
A lack of effective topical antimicrobial therapies available for Today’s health care providers as well as some shortcomings related to tissue toxicity and even poor solubility (in the case of silver sulfadiazine). As such, identifying an optimal antibacterial methodology for effectively treating infected diabetic foot ulcers remains a significant challenge. With an increasingly at risk population, and with increasingly strained healthcare resources, there is a need to develop new therapies for improving the treatment of these wounds.
BURN WOUND INFECTION: TOPICAL TREATMENT AND PREVENTION
Infection remains the most common and most serious complication of major burn injury. Despite improvements in burn wound management and antimicrobial therapy technologies, sepsis related to the burn accounts for 50-60% of deaths in burn patients today. Sepsis is commonly exhibited as pneumonia, pyelonephritis, thrombophlebitis, or invasive wound infection (31). The burn wound is ideal for bacterial growth and provides a perfect scenario for microbial invasion that increases with total burn surface area. Microbial colonization of burn wounds, occurs primarily from skin and then enteric flora and is usually established by the end of the first week. Infection is promoted by loss of the epithelial barrier, presence of dead tissue, by malnutrition induced by the hypermetabolic response to burn injury, and by a generalized post-burn immunosuppression due to release of immunoreactive agents from the burn wound. The severity of the burn, degree of immunosuppression, hypermetabolic response, and bacterial loading are significant challenges in burn treatment.
In military conflicts since World War II, burns have comprised roughly 8-10% of casualties sustained and vary based on the predominant type of weapon employed (32). As a result of the conflicts in Iraq and Afghanistan, the U.S. military has experienced unprecedented burn casualties, in number and severity. Improvements in resuscitation, transport, and in training permit the initial survival of individuals with burns approaching 80% total body surface area (TBSA). However, in an armed conflict setting, burned individuals still experience longer delays in reaching a burn center, and have a higher injury severity score than their civilian counterparts. Because they have lost the barrier function the skin normally provides, these individuals are profoundly immune suppressed and susceptible to infection. In addition, the massive skin damage sustained by these patients compromises their ability to regenerate skin quickly, which increases the infection risk and may lead to severe scarring and loss of function. Although major advances have been achieved in burn wound management, infection remains a leading cause of morbidity in burn patients. Infection can impede wound healing by directly damaging tissue and indirectly, by promoting an inappropriate and excessive inflammatory response. The wound also provides a protein-rich avascular and necrotic environment favoring microbial colonization and proliferation and impairing migration of immune cells and delivery of systemic antibiotics. Burn wound infection delays epidermal maturation and increases scarring. Microbial invasion below the dermis may also cause bacteremia, sepsis, and multiple-organ dysfunction syndrome.
In the wars in Iraq and Afghanistan, to date approximately 36,000 men and women have been wounded. Historically, 10% of those wounded in armed conflicts suffer burns with 20% of these being greater than 20% TBSA. In the United States approximately 2 million persons are burned annually resulting in 80,000 hospitalizations and 6,500 deaths (33). Even with the widespread use of currently available topical antimicrobial agents, wound sepsis remains the primary source of burn mortality (34). Thus, there is a critical need for the development of clinically acceptable treatment strategies that improve healing outcomes.
Within 48 hours of burn injury, gram-positive organisms, such as Staphylococcus aureus, heavily colonize the wound unless topical antimicrobials are used (35). After 5–7 days, other gram-positive organisms and gram-negative bacteria begin to populate these wounds. These organisms may be derived from the host’s gastrointestinal, upper respiratory flora or from the hospital environment. Yeasts and fungi may predominate later, due to use of broad-spectrum antibiotic therapy. Viruses, particularly Herpes simplex, have also been reported to be a problem in some burn units. Gram-negative organisms are now the most common bacteria implicated in invasive wound infections, due to their virulence and antimicrobial resistance. Organisms originating from the hospital environment tend to be more resistant than the patient’s normal flora. Emergence of bacterial resistance among a wide variety of pathogens limits treatment options for bacterial wound infections (35).
INNOVATION: Iasis Molecular Sciences (IMS) has developed several Multicomponent Active Pharmaceutical Ingredients (MAPIs) with controlled release behavior that are easily formulated as gels and ointments for topical application to treat and prevent infections associated lower extremity ulcers associated with venous insufficiency, diabetes, and burn wounds.
Department of the Army (Defense Medical Research and Development Program), Awarded 10/15/2016
Title: “A Novel Urinary Catheter with Tailorable Bactericidal Behavior”
Period of Performance: (3) Years
Department of the Army (Defense Medical Research and Development Program), Awarded 3/15/2011
Title: Topical Antimicrobial Agents with Tissue Protective Properties
Period of Performance: (3) Years
An FDA approved drug with unique chemical tailorability has shown considerable promise as a healing aid for the burn wound injury in early preclinical testing. Several derivatives of the drug have been shown to be effectively antimicrobial against several relevant wound pathogens and have been shown to be inhibitors of several neutrophil-derived proteases. Testing of an ointment formulated with several versions of the drug as a means of providing a multi-component chemotherapeutic approach to healing is proposed in an infected burn wound model. The studies are designed to provide an understanding of the capacity of these compounds to eliminate infection and improve healing.
This effort entails scaling up of the proposed active pharmaceutical ingredients (APIs), formulation onto topical formulations, and a preclinical evaluation to determine efficacy. The end-goal of this proposed work is to identify one or more active pharmaceutical ingredients (APIs) for proposed study in the human clinical environment as formulations for direct-to-wound chemotherapy that would minimize inflammation, eliminating bacterial loading, and reduce protease levels that can damage newly forming and existing viable tissue, growth factors, and cell-surface receptors necessary for effective wound healing.
A therapy based on the technology described in this proposal is elegantly simple, cost effective, and easy to store and handle. The formulations described in the proposed work could improve healing outcomes, including the preservation of tissues for those injured while deployed into zones of conflict around the globe.
National Institutes of Health (NIH): Novion Technologies has been awarded several phase 1 SBIR grants. The Institutes overseeing these awards include the National Institutes of: Allergy and Infectious diseases (NIAID), Diabetes, Digestive, and Kidney Diseases (NIDDK), General Medical Sciences (NIGMS), and the Heart, Lung, Blood Institute (NHLBI).
Currently, Novion Technologies has on-going research projects funded by NIDDK and NIAID. The NIDDK project is aimed at wound healing and infection associated with percutaneous devices including biosensors and central venous catheters and NIAID is funding a wound healing study using novel silver compounds.
REQUEST for INFORMATION:
Please direct inquiries to David J. Vachon, Ph.D.
1. Coffin SE, Zaoutis TE. Healthcare-Associated Infections. In: Long SS, Pickering LK, Prober CG. Principles and Practice of Pediatric Infectious Diseases. 3rd ed. Churchill Livingstone; 2008:chap 101.
2. Wenzel RP, Edmond MB. The impact of hospital-acquired bloodstream infections. Emerg Infect Dis. Mar-Apr 2001;7(2):174-7.
3. Klevens RM, Edwards JR, Richards CL, et al. Estimating healthcare-associated infections in US hospitals, 2002. Public Health Rep. Mar 2007;122(2):160-6.
4. Scott, R. D., The direct medical costs of healthcare-associated infections in US hospitals and the benefits of prevention, 2008. CDC. Available at http://www.cdc.gov/ncidod/dhqp/pdf/Scott_CostPaper.pdf.
5. Report: Vital signs: central line-associated blood stream infections–United States, 2001, 2008, and 2009. MMWR Morb Mortal Wkly Rep. Mar 4 2011;60(8):243-8.
6. Cardo, D., Dennehy,P.H., Halverson, P., Fishman, N., Kohn, M., Murphy, C.L., Whitley, M., Moving toward elimination of healthcare-associated infections: A call to action Am J Infect Control 2010;n:1-5.
7. Richards MJ, Edwards JR, Culver DH, Gaynes RP. Nosocomial infections in pediatric intensive care units in the United States. National Nosocomial Infections Surveillance System. Pediatrics. Apr 1999;103(4):e39.
8. Donlan, R. M., Biofilms and Device-Associated Infections, Emerging Infectious Diseases, Vol. 7, No. 2, March–April 2001, 277-281.
9. Chenoweth CE, Saint S. Infect Dis Clin North Am. 2011 Mar;25(1):103-15., Reviewed in Antimicrobial central venous catheters in adults: a systematic review and meta-analysis Urinary tract infections.
10. Maki DG Stolz SM, Wheeler S, Mermel LA. Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnated catheter. A randomized, controlled trial. Ann Intern Med 1997;127:257-66.
11. van Heerden PV, Webb SAR, Fong S, Golledges CL, Roberts BL, Thompson WR. Central venous catheters revisited-infection rates and an assessment of the new fibrin analyzing system brush. Anaesth Intens Care. 1996;24:330-3.
12. Hannan M, Juste R, Shankar U, Nightingale C, Axadian B, Soni N. Colonization of triple lumen catheters. A study on antiseptic bonded and standard catheters. Clin Intensive Care 1996;7:56.
13. Bach A, Schmidt H, Bottiger B, Schrieber B, Bohrer H, Motsch J, et al. Retention of antibacterial activity and bacterial colonization of antiseptic-bonded central venous catheters. J Antimicrob Chemother 1996;37:315-22.
14. Collin GR. ,Decreased catheter colonization through the use of an antiseptic-impregnated catheter. A continuous quality improvement project. Chest 1999;115:1632-40.
15. George SJ, Vuddamalay P, Boscoe MJ., Antiseptic-impregnated central venous catheters reduce the incidence of bacterial colonization and associated infection in immunocompromised transplant patients. Eur J Anaesthesiol 1997;14:428-31.
16. Saint S, Chenoweth CE. Biofilms and catheter-associated urinary tract infections. Infect Dis Clin North Am. 2003;17(2):411-432.
17. Maki, D.G., Tamya,P.A., Engineering Out the Risk of Infection with Urinary Catheters, Emerging Infectious Diseases, Vol. 7, No. 2, March–April 2001)
18. Mermel LA, Farr BM, Sherertz RJ, et al. Guidelines for the management of intravascular catheter-related infections, Infect Dis 2001 May 1; 32 (9): 1249-72)
19. O’Grady, N.P., Alexander, M., Dellinger, E.P., Gerberding, J.L., Heard, S.O., Maki, D.G., Masur, H., McCormick, R.D., Mermel, L.A., Pearson, M.L., Raad, I.I., Randolph, A., Weinstein, R.A. “Guidelines for the Prevention of Intravascular Catheter-related Infections.” The Centers for Disease Control, August 9, 2002, Vol. 51, No. RR10, pp. 1-26.
20. Economic costs of diabetes in the U.S. In 2007. Diabetes Care 2008; 31(3):596-615.
21 Boulton AJ, Meneses P, Ennis WJ. Diabetic foot ulcers: A framework for prevention and care. Wound Repair Regen 1999; 7(1):7-16.
22. Inoue N, Nishikata S, Furuya E, Takita H, Kawamura M, Nishikaze O. Streptozotocin diabetes: prolonged inflammatory response with delay in granuloma formation. Int J Tissue React 1985; 7(1):27-33.
23. Wetzler C, Kampfer H, Stallmeyer B, Pfeilschifter J, Frank S. Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair. J Invest Dermatol 2000; 115(2):245-253.
24. Reiber GE, Lipsky BA, Gibbons GW. The burden of diabetic foot ulcers. Am J Surg 1998; 176(2A Suppl):5S-10S.
25. (Lipsky BA, Armstrong DG, Citron DM, Tice AD, Morgenstern DE, Abramson MA. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, double-blinded, multicentre trial. Lancet. Nov 12 2005;366(9498):1695-703.
26. Lipsky BA, Giordano P, Choudhri S, Song J. Treating diabetic foot infections with sequential intravenous to oral moxifloxacin compared with piperacillin-tazobactam /amoxicillin-clavulanate. J Antimicrob Chemother. Aug 2007;60(2):370-6.
27. Lipsky BA, Stoutenburgh U. Daptomycin for treating infected diabetic foot ulcers: evidence from a randomized, controlled trial comparing daptomycin with vancomycin or semi-synthetic penicillins for complicated skin and skin-structure infections. J Antimicrob Chemother. Feb 2005;55(2):240-5.
28. Fitzgerald RH. What the Literature Reverals About Diabetic Foot Osteomyelitis. Podiatry Today [3 Mar 2009]. 2009. Ref Type: Electronic Citation
29. Reiber GE, Lipsky BA, Gibbons GW. The burden of diabetic foot ulcers. Am J Surg 1998; 176(2A Suppl):5S-10S.
30. Consensus development conference on diabetic foot wound care. 7-8 April 1999, Boston, MA. American Diabetes Association. Adv Wound Care 1999; 12(7):353-361.
31. Russell JA. Shock syndromes related to sepsis. In: Goldman L, Schafer AI, eds. Cecil Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap 108.
32. Ennis, J. L., K. K. Chung, E. M. Renz, D. J. Barillo, M. C. Albrecht, J. A. Jones, L. H. Blackbourne, L. C. Cancio, B. J. Eastridge, S. F. Flaherty, W. C. Dorlac, K. S. Kelleher, C. E. Wade, S. E. Wolf, D. H. Jenkins, and J. B. Holcomb. 2008. Joint Theater Trauma System implementation of burn resuscitation guidelines improves outcomes in severely burned military casualties. J Trauma 64:S146-S151.
33. 2004. Burns, p. 28.1-28.12. In Emergency War Surgery.
34. Murray, C. K. 2008. Epidemiology of infections associated with combat-related injuries in Iraq and Afghanistan. J.Trauma. 64:S232-S238.
35. Greenhalgh, D. G. 2009. Topical Antimicrobial Agents for Burn Wounds. Clin.Plastic Surg. 36:597-606.