The Canadian Institutes of Health Research response to antimicrobial resistance.

Antimicrobial resistance (AMR) has been a research priority for the Canadian Institutes of Health Research (CIHR), Institute of Infection and Immunity (III) since its inception, and a number of strategic research initiatives have been launched to address this global health problem by promoting and supporting research related to mechanisms and processes that impact the emergence and spread of resistance among individuals and within the environment. Here we will present research initiatives on AMR led by CIHR-III, which include national programs as well as international partnerships with the United Kingdom and the European Union, in addition to interesting outcomes of these initiatives.

Development of an infection-resistant vascular prosthesis.

To develop an infection-resistant arterial prosthesis, amikacin was bonded to 6-mm, uncrimped, filamentous velour prostheses using a collagen-release system. Infrarenal abdominal aortas were resected in 26 mongrel dogs. Thirteen dogs had their aortas replaced with the antibiotic-bonded grafts and 13 dogs had their aortas replaced with a graft containing collagen without antibiotics. Following closure of the abdominal incision, each dog received an intravenous infusion of 10(8) organisms of Staphylococcus aureus administered over a 30-minute interval. Three weeks after recovery from operation, the grafts were removed under aseptic conditions; all 13 (100%) of the control grafts were infected, but only one of 12 experimental grafts (8%) was infected. There were no adverse healing effects; to the contrary, there appeared to be accelerated development of a cellular neointima and fibroblastic infiltration to the interstices. Antibiotic bonding with a collagen-release system is a promising method for imparting infection resistance to a vascular prosthesis.

Prosthetic arterial graft material. Influence on neointimal healing and bacteremic infectibility.

Five commonly used prostheses were compared for susceptibility to bacteremic infection: US Catheter and Instrument Co (USCI) Ultralight weight knitted Dacron, USCI Sauvage filamentous velour Dacron, Meadox Microvel double velour knitted Dacron, polytetrafluoroethylene (PTFE)-Impra, and PTFE-Gore-tex. We used 6-mm diameter grafts to replace 4-cm segments of the abdominal aorta in 150 mongrel dogs. Fifteen dogs were used for each graft type and each healing interval: three and six months posttransplantation. At the appropriate time after implantation, an intravenous infusion of 10(8) organisms of Staphylococcus aureus was administered to the ten experimental dogs in each graft type; five dogs of each graft type served as sterile controls. Three weeks later, the grafts were aseptically removed, inspected for the completeness of neointimal healing, and cultured for bacteria. At three months, the Sauvage graft achieved the lowest infection rate (10%) with the highest incidence of complete neointimal lining (71%). In the six-month series, there were no statistical differences between the knitted Dacron prostheses, but all Dacron grafts were superior to the PTFE grafts with regard to susceptibility to bacteremic infection and completeness of intimal lining.

Collagen fibers as a fleece hemostatic agent.

The hemostatic efficacy of collagen fibers as a fleece hemostatic agent (CFH) is compared with the efficacy of three commercially available agents: collagen powder (Avitene), absorbable gelatin sponge, and oxidized cellulose. Identical quantities of the four materials were applied to identical multiple spleen incisions in five dogs; CFH and collagen powder proved three times as effective as the other two mateials. CFH and collagen powder were then compared with regard to hemostatic efficacy, handling characteristics, and tissue reaction. Different weights of the materials were applied to multiple spleen lacerations in 12 dogs and spleen avulsions in 12 dogs. The hemostatic efficacy of the materials was similar, but CFH was superior with regard to handling characteristics and tissue reaction. Another experiment, with six pigs, showed that CFH can be successfully sutured as a patch to profusely bleeding lacerations of the spleen, liver, and kidney.

The fibrinolytic system. A key to tumor metastasis?

Neither histologic nor clinical staging reliably correlates with patient survival or the time course of tumor metastatic spread. There is no general biologic tumor marker which is able to distinguish those patients with microscopic residual cancer who may benefit from adjuvant anticancer treatment from those patients cured by their primary treatment who do not require additional anticancer therapy. Our data suggest that tumor activation and inhibition of fibrinolysis are related to the likelihood of tumor spread. Calculation of mean activation/inhibition ratios (A/I ratios) in groups of tumors with and without metastatic spread demonstrated a statistically significant difference between their respective A/I ratios (p less than 0.001). In addition, the mean activation/inhibition ratios for secondary or "metastatic" lesions were significantly different from the mean activation/inhibition ratios of the original tumors from which they metastasized (p less than 0.001). Therefore, tumor activation/inhibition ratios would appear to have clinical reliability as biologic markers for the presence or absence of tumor metastases. These data may have important therapeutic implications that would permit the use of activation/inhibition ratios as a biologic marker for the presence or absence of tumor spread at the time of primary surgical excision of the tumor. These observations warrant further investigation into the mechanisms of tumor interaction with the fibrinolytic system.