Background: Combat-related injuries are generally complex and are frequently associated with extensive tissue destruction. Such wounds place injured combatants at high risk for infectious complications. Recent wars in Iraq and Afghanistan have resulted in ~43,000 wounded personnel highlighting the ongoing need for wound care. A variety of wounds are encountered in the theatre including those involving extensive tissue damage and punctures. Burn patients constitute approximately 5% of military casualties, and such wounds frequently become infected with bacterial and fungal pathogens. Prophylactic antibiotics are recommended for certain types of would infections, while for others, such as burns, topical antimicrobial agents are more appropriate. However, in recent years, infecting organisms are frequently resistant to one or more antibiotics (or antifungals), which creates a life-threatening condition. The most notable drug-resistant infections are caused by Acinetobacter baumannii-calcoaceticus complex (ABC), extended spectrum beta-lactamase-producing bacteria Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), Enterobacter spp and Pseudomonas aeruginosa. Fungal infections due to Candida and Aspergillus species, and other molds, are increasingly recognized as a cause of infection. Drug-resistant pathogens increase mortality and morbidity. Topical antimicrobial agents in theatre can improve the outcome of seriously injured soldiers by limiting infection. Unfortunately, there are imperfect options currently available to treat drug-resistant bacteria and fungi with a single safe reagent. There is a need for better topical agents that are effective against a wide range of drug-resistant bacteria and fungi and can be deployed in theatre to limit or eliminate wound infections in military personnel after sustaining injury.Objective/Hypothesis: The objective of this study is to demonstrate the potent antimicrobial properties of carbohydrate-derived fulvic acid (CHD-FA) against a broad collection of drug-sensitive and multidrug-resistant bacterial and fungal pathogens commonly associated with wound infections and assess the relative efficacy of CHD-FA against induced wound infections in animal models. Preliminary studies support the broad antimicrobial properties for CHD-FA, its strong safety profile, anti-inflammatory property, and promotion of wound health. Given its novel mechanism of action, early use of CHD-FA is an advantage because it will not select for known resistant organisms.Specific Aims: (1) Establish minimum inhibitory concentrations (MIC50 and MIC90) for CDH-FA against large collections of clinical isolates representing wound-associated drug-resistant bacteria and fungi. (2) Small animal models of wound infection with a wide variety of bacterial and fungal pathogens will be evaluated by topical application of CDH-FA.Study Design: CHD-FA MIC50 and MIC90 values will be determined according to CLSI methodology for 50-100 clinical isolates of Acinetobacter baumannii, Pseudomonas aeruginosa, carbapenamase-resistant Klebsiella pneumoniae, Enterococcus faecium, Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus, Escherichia coli, Enterobacter spp., as well as azole-resistant fungal pathogens Aspergillus fumigates and polyene-resistant non-fumigatus Aspergillus species, Fusarium species, and Zygomycetes.Rat models of wound infection (open, burn, and deep tissue) will be established with healthy animals using drug-resistant bacterial and fungal pathogens. Increasing doses of CDH-FA in topical form will be used to assess relative efficacy with end points being prevention of enlarging lesions, reduction of microbial burden, reduced inflammation, healing, and molecular cellular markers of recovery. All experiments will compare infected/uninfected and treated/untreated wounds relative to existing antimicrobial agents.Clinical Impact: The use of CHD-FA as a topical broad-spectrum antimicrobial agent that can overcome or prevent drug-resistant bacterial and fungal infections in patients with serious wounds is a significant advance for both military and civilian populations, especially high-risk patients such as those with burn wounds.Military Relevance: CHD-FA is well suited to combat personnel in theatre because wounds are exposed to a wide range of potential pathogens in the environment, and there is a need for a rapidly deployable, safe, stable, and effective countermeasure to sterilize or limit infections due to drug-resistant pathogens.
|Effective start/end date||9/30/12 → 9/29/15|
- Congressionally Directed Medical Research Programs (CDMRP)