The impact of antibiotic stewardship interventions and patient related factors on antibiotic prescribing in a vascular surgical department.

PURPOSE: The development of guidelines tailored to the departments' needs and counselling during ward rounds are important antibiotic stewardship (AS) strategies. The aim was to analyse the impact of AS ward rounds and institutional guidelines as well as patient-related factors on antibiotic use in vascular surgical patients. METHODS: A retrospective prescribing-analysis of 3 months (P1, P2) before and after implementing weekly AS ward rounds and antimicrobial treatment guidelines was performed. Choice of systemic antibiotics, days of antibiotic therapy and clinical data were obtained from electronic patient records. RESULTS: During P2, the overall antibiotic consumption as well as the use of last-resort compounds like linezolid and fluoroquinolones decreased distinctly (overall: 47.0 days of therapy (DOT)/100 patient days (PD) vs. 35.3 DOT/100PD, linezolid: 3.7 DOT/100PD vs. 1.0 DOT/100PD, fluoroquinolones: 7.0 DOT/100PD vs. 3.2 DOT/100PD) while narrow-spectrum beta-lactams increased by 48.4%. Courses of antibiotics were de-escalated more often during P2 (30.5% vs. 12.1%, p = 0.011). Only in P2, an antibiotic therapy was initiated in patients suffering from more comorbidities (i.e. higher Charlson Comorbidity Index) more frequently. Other patient factors had no distinct impact on antibiotic prescribing. CONCLUSION: Weekly AS ward rounds improved adherence to institutional antibiotic treatment guidelines and antibiotic prescribing in vascular surgical patients. Clear patient-related determinants affecting choice of antibiotic therapies could not be identified.

Connective tissue structures in clubfoot: a morphologic study.

A morphologic study of connective tissue structures in clubfoot, with special emphasis on the presence of myofibroblasts, was undertaken to investigate the theory of retracting fibrosis as an etiologic factor. Nine idiopathic clubfeet from six patients were studied. Specimens from the medial and lateral capsule, medial and lateral fascia, spring and lacinate ligaments, and flexor digitorum longus, flexor hallucis longus, posterior tibialis, and Achilles tendon sheaths were investigated. Fifty specimens were examined using light microscopy and hematoxylin and eosin staining, and 26 were examined by transmission electron microscopy. Light microscopy failed to reveal any myofibroblast-like cells or any qualitative differences between specimens from capsule, fascia, ligaments, and tendon sheath. Using transmission electron microscopy, the authors identified two cell types: fibroblasts and mast cells. Some fibroblasts contained a network of microfilaments but all lacked microbundles, basal lamina, or plasmalemmal attachment plaques seen in typical myofibroblasts. Mast cells were rarely identified in capsular specimens. The absence of myofibroblast-like cells or typical myofibroblasts in clubfoot connective tissue structures does not support the theory of retracting fibrosis as a likely cause of contracture in idiopathic clubfoot.

Targeting tumor cells with bispecific antibodies and T cells.

It has been known for some time that mammalian immune systems are capable of eliminating large tumor burdens. Redirecting the immune response of a patient to an established tumor has now become the focus of various therapeutic strategies. In this report, two projects toward this goal are described. The first project involves the development of a transgenic mouse model for T cell directed therapeutics. These mice express specific T cell receptor alpha and beta transgenes on a background in which the recombinational-activating-gene-1 (RAG) has been knocked out. The mice express cytotoxic T cells but not either T helper cells or B cells. Despite these deficiencies, the animals are capable of eliminating tumors that express the appropriate peptide/major histocompatibility complex ligand that is recognized by the alphabeta transgenic T cell receptor. Human tumors grow as transplants in these mice, thereby allowing various agents that redirect the endogenous T cells against human tumors to be tested. The second project involves a description of such agents: bispecific antibodies that simultaneously bind to an immune effector cell and a tumor cell. The bispecific antibody described here consists of folate attached to anti-T cell receptor antibodies, or their fragments. A single-chain Fv coupled with folate can redirect the lysis of human tumor cells that bear the high affinity folate receptor. Preliminary in vivo data showed that the folate/antibody conjugates were also capable of mediating rejection of the human tumor. This transgenic mouse model should now allow the evaluation and optimization of bispecific agents that can redirect a patient's own T cell response.

Antigen recognition and allogeneic tumor rejection in CD8+ TCR transgenic/RAG(-/-) mice.

Three sources of help for the development of a CD8+ CTL response have been described: the CD4+ direct and indirect pathways and the CD8+ direct pathway. In an effort to understand the minimal requirements for the development of a CTL response in vivo, we have bred mice transgenic for the 2C TCR onto a RAG(-/-) background. The 2C T cells in this animal are exclusively CD8+ CTLs of a single specificity, and they exhibit altered thymic maturation compared with that of T cells from 2C TCR/RAG(+/+) mice. T cells from 2C TCR/RAG(-/-) mice can be activated to a high level in vivo by administration of a self-MHC-restricted antigenic peptide. The 2C TCR/RAG(-/-) mice are able to reject B7-negative allogeneic tumors bearing the appropriate peptide/MHC ligand p2C/Ld. These mice fail to reject syngeneic tumors, and their RAG(-/-) littermates lacking 2C T cells uniformly succumb to both allogeneic and syngeneic tumors. Moreover, blockade of B7 costimulatory molecules fails to prevent tumor rejection in the 2C TCR/RAG(-/-) mice, suggesting that allorejection is occurring independently of B7-mediated costimulation as well as in the absence of CD4+ T cells. CTLs isolated from the site of the tumor during the period of rejection express the activation marker CD25 and are able to mediate ex vivo cytolysis of tumor cells bearing the appropriate Ag. These results suggest that in this TCR transgenic model with a very high precursor frequency, CTL development can occur in the absence of B7:CD28 costimulation and without CD4+ help.