Despite current infection intervention strategies implemented to treat combat-related injuries, one-third of such injuries are complicated by infections. Infections acquired during active duty or while being treated at Department of Defense facilities or various healthcare facilities have been found to persist after patients enter a VA facility. There has been an increase in the complexity of infectious disease management reported on Veterans who suffered from combat wounds obtained during the Gulf War era. The rise in antibiotic-resistant bacterial infections presents a threat to public health and the economy. Approximately one-third of Veterans admitted to VA acute care medical facilities have both multi-drug resistant Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). Patients colonized with these pathogens can bring the organism into hospitals and long-term facilities where it can spread and infect susceptible patients. Patients suffering from infections by these multi-drug resistant organisms (MDRO's) result in higher treatment costs, longer hospital stays, and higher rates of mortality compared to patients with susceptible bacterial infections. There is a need to investigate alternative or complimentary treatments to the currently available therapies such as the use of last-resort antibiotics. We hypothesize that a combination of a phage cocktail AND anti- Staphylococci and antipseudomonal antibiotics delivered in a hydrogel can be developed to prevent and treat polymicrobial wound infections. We propose to do this by: 1) Determine the optimal formulation of phage- antibiotic combination (PAC) treatment in vitro. Cefepime, vancomycin and a phage cocktail (i.e., phages against Staphylococci and Pseudomonas) will be formulated and tested against clinical strains to determine optimal concentrations of the antibacterial agents needed to kill the target bacteria. The release rate of the drugs and phages from a hydrogel will be determined. We will then: 2) Develop a polymicrobial wound infection in a rat model by establishing a subcutaneous wound infection caused by both MRSA and P. aeruginosa over a 14-day period. Bioluminescent bacteria will be used to develop a polymicrobial wound infection (i.e. cutaneous abscess), which will be monitored in real-time using an in vivo imaging system. Lastly, we will: 3) Assess the efficacy of locally administered PAC at treating wound infection in a rat wound model. Our polymicrobial wound infection model will be used to the test the efficacy of the following treatments: a) single dose of locally administered PAC hydrogel; b) repeated doses of locally delivered PAC hydrogel; c) systemic administration of liquid PAC administered every 12 hours; d) placebo (i.e. saline in hydrogel) delivered locally administered every 12 hours. Parameters assessed will include level of bacterial bioluminescence, gross wound appearance and renal function over time. Bacterial counts in the wound at the completion of treatment will also be assessed. Our phage and antibiotic combination (PAC) hydrogel will provide the requisite local concentrations of antibacterial agents to kill MRSA and P. aeruginosa while minimizing systemic concentrations and the associated undesirable side effects. Our goal is to formulate the optimum concentration of phages and antibiotics in a hydrogel and assess the feasibility and efficacy to treat polymicrobial wound infections in a rat wound model. The development of our PAC treatment could have a profound impact on the medical community by presenting an alternative treatment to control difficult bacterial infections caused by multi-drug resistant organisms.
Approximately one-third of Veterans admitted to VA acute care medical facilities suffer from infections caused by multidrug-resistant organisms. Patients colonized with these bacteria can bring them into hospitals and long-term care facilities where they can spread and infect susceptible patients. Patients suffering from infections by these multidrug-resistant organisms result in higher treatment costs, longer hospital stays, and higher rates of mortality compared to patients with susceptible bacterial infections. Our pre-clinical research focuses on assessing the feasibility and efficacy of locally delivering our phage and antibiotic combination (PAC) therapy to treat polymicrobial wound infections, while minimizing systemic concentrations and the associated undesirable side effects seen when using last-resort antibiotics. This research can have a direct beneficial effect to the quality of care provided to Veterans and the nation who suffer from skin and soft tissue infections caused by multidrug-resistant organisms.
